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Information on EC 3.4.21.61 - Kexin
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3.4.21.61 KexinSpecify your search results
Word Map
- 3.4.21.61
- cholesterol
- lipoprotein
- cardiovascular
-
low-density
- statin
- hypercholesterolemia
- coronary
-
lipid-lowering
- atherosclerotic
- ezetimibe
-
evolocumab
-
alirocumab
- furin
- artery
-
apolipoprotein
- triglyceride
-
ldl-cholesterol
- dyslipidemias
- myocardial
-
placebo
- stroke
-
high-risk
-
ascvd
- infarction
-
atherogenic
- hyperlipidemia
- atorvastatin
-
cholesterol-lowering
- intolerance
-
lipoprotein-cholesterol
- hdl
-
cardiology
-
apheresis
- diagnostics
-
non-high-density
-
ldl-receptors
-
angiopoietin-like
- proinsulin
- proopiomelanocortin
-
treatment-emergent
- srebp-2
-
endoproteolytic
-
guideline-recommended
-
triglyceride-rich
- drug development
- prodomain
- endoproteases
- degradation
-
non-hdl-c
-
fibrates
- xanthoma
-
statin-treated
- molecular biology
- medicine
- niacin
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
pcsk9, proprotein convertase subtilisin/kexin type 9, proprotein convertase, pc1/3, kexin, kex2p, pcsk6, prohormone convertase 1, proprotein convertase subtilisin kexin type 9, prohormone convertase 2, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
adrenorphin-Gly-generating enzyme
-
-
-
-
EC 3.4.22.23
-
-
formerly
-
endoproteinase Kex2p
-
-
-
-
Gene KEX2 dibasic proteinase
-
-
-
-
Kex 2p proteinase
-
-
-
-
Kex2
Kex2 endopeptidase
-
-
-
-
Kex2 endoprotease
-
-
-
-
Kex2 endoproteinase
-
-
-
-
Kex2 protease
-
-
-
-
Kex2 proteinase
-
-
-
-
Kex2-like endoproteinase
-
-
-
-
Kex2-like precursor protein processing endoprotease
-
-
-
-
Paired-basic endopeptidase
-
-
-
-
PC 1/3
PCSK type 9
PCSK6
PCSK9
pro-protein convertase subtilisin/kexin type 9
prohormone convertase 1/3
Prohormone-processing endoprotease
-
-
-
-
Prohormone-processing KEX2 proteinase
-
-
-
-
Prohormone-processing proteinase
-
-
-
-
Proprotein convertase
-
-
-
-
proprotein convertase subtilisin kexin type 9
proprotein convertase subtilisin/kexin type 9
proprotein convertase subtilisin/kexin type 9 (PCSK9)Proprotein convertase subtilisin/kexin type 9
Protease KEX2
-
-
-
-
Proteinase Kex2p
-
-
-
-
Proteinase yscF
-
-
-
-
Proteinase, prohormone-processing
-
-
-
-
Yeast KEX2 protease
-
-
-
-
additional information
PCSK9
-
proprotein convertase subtilisin/kexin type 9
-
proprotein convertase subtilisin/kexin type 9 (PCSK9)Proprotein convertase subtilisin/kexin type 9
-
-
proprotein convertase subtilisin/kexin type 9 (PCSK9)Proprotein convertase subtilisin/kexin type 9
-
-
proprotein convertase subtilisin/kexin type 9 (PCSK9)Proprotein convertase subtilisin/kexin type 9
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cleavage of -Lys-Arg-/- and -Arg-Arg-/- bonds to process yeast alpha-factor pheromone and killer toxin precursors
Cleavage of -Lys-Arg-/- and -Arg-Arg-/- bonds to process yeast alpha-factor pheromone and killer toxin precursors
cleavage of-Lys-Arg-+- and Arg-Arg-+- bonds to process yeast alpha-factor pheromone and killer toxin precursors, the term -+- depicts the point of cleavage
-
-
-
Cleavage of -Lys-Arg-/- and -Arg-Arg-/- bonds to process yeast alpha-factor pheromone and killer toxin precursors
catalytic residues are D175, H213, S385
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
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CAS REGISTRY NUMBER
COMMENTARY
99676-46-7
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Ac-(beta-cyclohexyl)alanineYKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-(beta-cyclohexyl)alanineYKK
-
-
-
?
Ac-Ala-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + ?
-
-
-
?
Ac-Ala-Tyr-Lys-Lys 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + ?
-
-
-
?
Ac-alpha-aminobutyric acid-YKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-alpha-aminobutyric acid-YKK
-
-
-
?
Ac-Arg-Tyr-Lys-Lys 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Arg-Tyr-Lys-Lys
-
-
-
?
Ac-AYKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-AYKK
-
-
-
?
Ac-AYKR 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-AYKR
-
-
-
?
Ac-Cit-Tyr-Lys-Lys 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Cit-Tyr-Lys-Lys 4-methylcoumarin
-
this substrate is cleaved poorly
-
?
Ac-CYKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-CYKK
-
-
-
?
Ac-FYKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-FYKK
-
-
-
?
Ac-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Nle-Tyr-Lys-Arg-COOH
Ac-Nle-Tyr-Lys-Lys 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + ?
-
-
-
?
Ac-Nle-YKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Nle-YKK
-
-
-
?
Ac-Nle-YKR 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + ?
-
-
-
?
Ac-Nle-YKR 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Nle-YKR
-
-
-
?
Ac-norvaline-YKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-norvaline-YKK
-
-
-
?
Ac-Pro-Met-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + ?
-
-
-
?
Ac-Pro-Met-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Pro-Met-Tyr-Lys-Arg
-
-
-
?
Ac-RYKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-RYKK
-
-
-
?
Ac-VYKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-VYKK
-
-
-
?
Arg-Lys(DABCYL)-Nle-Tyr-Lys-Arg-Glu-Ala-Glu-Ala-Glu(EDANS)-Arg + H2O
Arg-Lys(DABCYL)-Nle-Tyr-Lys-Arg + Glu-Ala-Glu-Ala-Glu(EDANS)-Arg
-
-
-
?
Arg-Lys(DABCYL)-Nle-Tyr-Lys-Lys-Glu-Ala-Glu-Ala-Glu(EDANS)-Arg + H2O
Arg-Lys(DABCYL)-Nle-Tyr-Lys-Lys + Glu-Ala-Glu-Ala-Glu(EDANS)-Arg
-
-
-
?
benzyloxycarbonyl-Ala-Tyr-Lys-Lys 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + benzyloxycarbonyl-Ala-Tyr-Lys-Lys
-
-
-
?
benzyloxycarbonyl-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
?
-
-
-
?
benzyloxycarbonyl-Nle-Tyr-Lys-Lys 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Cbz-Nle-Tyr-Lys-Lys
-
-
-
?
benzyloxycarbonyl-Nle-YKR 4-methylcoumarin 7-amide + H2O
?
-
-
-
?
CLC chloride channel + H2O
proteolytically processed CLC chloride channel
-
cleavage in first intracellular loop at residues K136/R137
-
-
?
D-Ac-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
?
-
-
-
?
L-pyroglutamyl-Arg-Thr-Lys-Arg-4-methylcoumaryl-7-amide + H2O
L-pyroglutamyl-Arg-Thr-Lys-Arg + 7-amino-4-methyl-coumarin
-
-
-
-
?
low-density lipoprotein receptor
?
PCSK9 posttranslationally promotes the degradation of the low-density lipoprotein receptor
-
-
?
N-tert-butyloxycarbonyl-Gly-Lys-Arg 4-methylcoumarin 7-amide + H2O
N-tert-butyloxycarbonyl-Gly-Lys-Arg + 7-amino-4-methylcoumarin
-
59.2% of the activity with tert-butyloxycarbonyl-Gln-Arg-Arg 4-methylcoumarin 7-amide
-
-
?
pGlu-Arg-Thr-Lys-Arg-4-methylcoumaryl-7-amide + H2O
7-amino-4-methylcoumarin
-
-
-
-
?
prekallikrein
?
-
cleaved into four fragments by ASP, protein cleaved at specific sequences
-
-
?
Proinsulin + H2O
Insulin + ?
-
cleaves human proinsulin at the peptide bond between Arg32 and Glu33
-
?
proopiomelanocortin + H2O
beta-lipotropic hormone + adrenocorticotropic hormone + ?
-
-
-
-
?
t-butyloxycarbonyl-Arg-Val-Arg-Arg-4-methylcoumaryl-7-amide + H2O
t-butyloxycarbonyl-Arg-Val-Arg-Arg + 7-amino-4-methyl-coumarin
-
-
-
-
?
t-butyloxycarbonyl-EKK 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + t-butyloxycarbonyl-EKK
-
-
-
?
t-butyloxycarbonyl-Glu-Lys-Lys-4-methylcoumaryl-7-amide + H2O
t-butyloxycarbonyl-Glu-Lys-Lys + 7-amino-4-methyl-coumarin
-
best substrate
-
-
?
t-butyloxycarbonyl-Gly-Lys-Arg-4-methylcoumaryl-7-amide + H2O
t-butyloxycarbonyl-Gly-Lys-Arg + 7-amino-4-methyl-coumarin
-
-
-
-
?
t-butyloxycarbonyl-QGR 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + t-butyloxycarbonyl-QGR
-
-
-
?
tert-Butyloxycarbonyl-Ala-Pro-Arg 4-methylcoumarin 7-amide + H2O
?
-
17% of the activity with tert-butyloxycarbonyl-Gln-Arg-Arg 4-methylcoumarin 7-amide
-
-
?
tert-butyloxycarbonyl-Gln-Arg-Arg 4-methylcoumarin 7-amide + H2O
tert-butyloxycarbonyl-Gln-Arg-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
tert-Butyloxycarbonyl-Leu-Arg-Arg 4-methylcoumarin 7-amide + H2O
?
-
116% of the activity with tert-butyloxycarbonyl-Gln-Arg-Arg 4-methylcoumarin 7-amide
-
-
?
tert-Butyloxycarbonyl-Leu-Lys-Arg 4-methylcoumarin 7-amide + H2O
?
-
92.8% of the activity with tert-butyloxycarbonyl-Gln-Arg-Arg 4-methylcoumarin 7-amide
-
-
?
tert-Butyloxycarbonyl-Val-Pro-Arg 4-methylcoumarin 7-amide + H2O
?
-
38% of the activity with tert-butyloxycarbonyl-Gln-Arg-Arg 4-methylcoumarin 7-amide
-
-
?
Ac-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Nle-Tyr-Lys-Arg-COOH
-
-
-
?
Ac-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide + H2O
7-amino-4-methylcoumarin + Ac-Nle-Tyr-Lys-Arg-COOH
-
-
-
?
low density lipoprotein receptor + H2O
?
-
C-terminal domain of enzyme has a stronger affinity for substrate low density lipoprotein receptor than catalytic domain. A C-terminal deletion mutant does not mediate low density lipoprotein receptor degradation
-
-
?
low density lipoprotein receptor + H2O
?
-
PCSK9 binding to cell surface low density lipoprotein receptor cannot be described by a simple bimolecular reaction. Data suggest the presence of two populations of binding site
-
-
?
low density lipoprotein receptor + H2O
?
-
a discrete C-terminal protein fragment competes with full-length PCSK9 for binding to LDLR in vitro and attenuates PCSK9-mediated hypercholesterolemia in mice
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
-
degradation
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
-
the enzyme acts on the extracellular domain of the receptor molecule
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
degradation
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
-
the enzyme acts on the extracellular domain of the receptor molecule
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
degradation
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
the enzyme acts on the extracellular domain of the receptor molecule
-
-
?
Precursor protein of the mating hormone alpha-factor of Saccharomyces cerevisiae + H2O
?
-
processing
-
-
?
Precursor protein of the mating hormone alpha-factor of Saccharomyces cerevisiae + H2O
?
-
processing
-
-
?
pro-alpha-mating factor + H2O
alpha-mating factor + ?
-
-
-
?
pro-alpha-mating factor + H2O
alpha-mating factor + ?
-
-
-
?
pro-alpha-mating factor + H2O
alpha-mating factor + ?
-
mating pheromone precursor, physiological substrate
-
?
Protein + H2O
?
-
specificity: preference for Lys-Arg, while Arg-Arg, Pro-Arg, Ala-Arg, and Thr-Arg are equally rapidly cleaved but with higher Km
-
-
?
Protein + H2O
?
-
autocatalytic activation at an internal Lys108-Arg109
-
-
?
Protein + H2O
?
-
precursor protein of the mating hormone alpha-factor of Saccharomyces cerevisiae
-
-
?
Protein + H2O
?
-
specificity towards the carbonyl side of Lys-Arg, Arg-Arg and Pro-Arg sequences
-
-
?
Protein + H2O
?
-
cleaves a wide variety of precursors from higher eukaryotes including prohormones, such as proinsulin and proopiomelanocortin, as well as precursors of constitutively secreteted proteins, such as proalbumin
-
-
?
additional information
?
-
-
FRETS-25Xaa libraries as substrates. Best FRETS contains Lys at position Xaa (FRETS-25K). No cleavage of succinyl-Ala-Ala-Pro-Phe-4-methylylcoumaryl-7-amide, t-butyloxycarbonyl-Gly-Arg-Arg-4-methylylcoumaryl-7-amide, Z-His-Glu-Lys-4-methylylcoumaryl-7-amide, and t-butyloxycarbonyl-Phe-Ser-Arg-4-methylylcoumaryl-7-amide
-
-
?
additional information
?
-
both furinand hepsin-cleaved enzymes are able to degrade LDL receptor on HepG2 cells resulting in elevated serum cholesterol levels
-
-
?
additional information
?
-
the enzyme catalytic domain is capable of proteolysis in trans (i.e. as two separate polypeptides), and can perform intermolecular proteolysis
-
-
?
additional information
?
-
-
CT-peptide is not cleaved by enzymatically active PC1/3
-
-
?
additional information
?
-
-
a variety of trypsin substrates containing only one basic amino acid
-
-
?
additional information
?
-
-
cleaves peptide substrates at both Lys-Arg and Arg-Arg sites, not: benzyloxycarbonyl-Lys-Arg 4-nitroanilide, benzyloxycarbonyl-Arg-Arg 4-nitroanilide
-
-
?
additional information
?
-
-
exhibits optimal activity toward substrates with Lys or Arg at P2 and Arg at P1, also recognizes P4, with dual specificity for aliphatic and basic residues
-
?
additional information
?
-
-
generates peptide hormone by specific processing of propeptides
-
?
additional information
?
-
-
hydrolyzes peptides and proteins with basic amino acid pairs which are cleaved at the C-ends of their peptide bonds, cleaves specifically large recombinant proteins, for example a protein consisting of a gamma-interferon fragment linked to HIV1-proteinase via a Lys-Arg-containing peptide
-
?
additional information
?
-
-
carries out specific endoproteolytic cleavage of proprotein and prohormone precursors in the secretory pathway, hydrolyzes ester and amide substrates
-
?
additional information
?
-
-
transforming the precursors of biologically active agents into their functional forms, processing and conversion of prohormones
-
?
additional information
?
-
-
wild-type, preference for positively charged residues at P2 position. Mutant D176G/D210A/D211S, preference for MR- over LR- or FR-containing substrates, which cannot be cleaved by wild-type
-
-
?
additional information
?
-
-
a variety of trypsin substrates containing only one basic amino acid
-
-
?
additional information
?
-
-
cleaves peptide substrates at both Lys-Arg and Arg-Arg sites, not: benzyloxycarbonyl-Lys-Arg 4-nitroanilide, benzyloxycarbonyl-Arg-Arg 4-nitroanilide
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
CLC chloride channel + H2O
proteolytically processed CLC chloride channel
-
cleavage in first intracellular loop at residues K136/R137
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
-
degradation
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
degradation
-
-
?
low density lipoprotein receptor-related protein 1 + H2O
?
degradation
-
-
?
Precursor protein of the mating hormone alpha-factor of Saccharomyces cerevisiae + H2O
?
-
processing
-
-
?
Precursor protein of the mating hormone alpha-factor of Saccharomyces cerevisiae + H2O
?
-
processing
-
-
?
pro-alpha-mating factor + H2O
alpha-mating factor + ?
-
-
-
?
pro-alpha-mating factor + H2O
alpha-mating factor + ?
-
mating pheromone precursor, physiological substrate
-
?
additional information
?
-
both furinand hepsin-cleaved enzymes are able to degrade LDL receptor on HepG2 cells resulting in elevated serum cholesterol levels
-
-
?
additional information
?
-
-
generates peptide hormone by specific processing of propeptides
-
?
additional information
?
-
-
carries out specific endoproteolytic cleavage of proprotein and prohormone precursors in the secretory pathway, hydrolyzes ester and amide substrates
-
?
additional information
?
-
-
transforming the precursors of biologically active agents into their functional forms, processing and conversion of prohormones
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
additional information
no effect with Mg2+, Mn2+, Co3+, and Fe3+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(3S,4S,5S,6R)-2-([(2R,3S,4S,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-4-yl]amino)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol
-
i.e. BJ-12-26-1, greatly reduces the processing of substrate proopiomelanocortin
(3S,4S,5S,6R)-2-([(2S,3S,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3-yl]amino)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol
-
i.e. BJ-12-21-2, greatly reduces the processing of substrate proopiomelanocortin
5alpha,6alpha-epoxy-(22E,24R)-ergosta-8(14),22-diene-3beta,7beta-diol
isolated from fruiting bodies of Sparassis crispa
Ac-R-E-R-K-chloromethylketone
-
alternate binding site and resultant displacement of the scissile bond in the active site results in a decrease in the acylation rate
ISIS 394814
-
most potent antisense oligonucleotide. Administration to high fat-fed mice for 6 weeks reduces hepatic PCSK9 mRNA levels by 92%, total cholesterol and LDL by 53% and 38%, respectively. Inhibition of PCSK9 expression results in a 2fold increase in hepatic LDLR protein levels
-
propeptide
-
addition of purified recombinant propeptide (20 nanomol) to PC1/3 enzymatic reaction leads to a 50% reduction in enzymatic activity. In the presence of 5 nanomol CT-peptide and 20 nanomol propeptide, inhibition is reduced to 35%
-
additional information
-
Dpy-5 suppresses the adult-specific blistering by BLI-4. Dpy-5 dominant suppression of the BLI-4 phenotype differs between the sexes, being incomplete in males
-
additional information
-
PC5A inactivates PCSK9 via direct and indirect cleavages. PC5A, furin, or ADAMTS-4, but not ADAMTS-5, generate a 34-kDa PCSK9 product
-
additional information
-
splicing variant of PCSK9 has no specific effect impacting wild-type PCSK9 function
-
additional information
in HEK-293 and Hep-G2 cells, 1G08 fragment antigen binding reduces 50% the PCSK9-dependent inhibitory effects on low density lipoprotein uptake. 1G08 fragment antigen binding does not affect the PCSK9-low density lipoprotein receptor interaction but inhibits the internalization of PCSK9 in these cells. 1G08 fragment antigen binding binds a region of beta-strands encompassing Arg-549, Arg-580, Arg-582, Glu-607, Lys-609, and Glu-612 in the PCSK9 C-terminal domain. The membrane associated protein Annexin A2 does not affect 1G08-PCSK9 binding
-
additional information
human monoclonal antibody against PCSK9, mAb1, inhibits PCSK9 binding to the low density lipoprotein receptor and attenuates PCSK9-mediated reduction in low density lipoprotein receptor protein levels, thereby increasing low density lipoprotein uptake. A combination of mAb1 with a statin increases low density lipoprotein receptor levels in Hep-G2 cells more than either treatment alone
-
additional information
clinical antibody studies, with alirocumab and evolocumab, overview
-
additional information
areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor
-
additional information
-
areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor
-
additional information
-
human monoclonal antibody against PCSK9, mAb1, inhibits PCSK9 binding to the low density lipoprotein receptor and attenuates PCSK9-mediated reduction in low density lipoprotein receptor protein levels, thereby increasing low density lipoprotein uptake. A single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days
-
additional information
-
PCSK9 protein and mRNA are decreased significantly by fasting
-
additional information
-
human monoclonal antibody against PCSK9, mAb1, inhibits PCSK9 binding to the low density lipoprotein receptor and attenuates PCSK9-mediated reduction in low density lipoprotein receptor protein levels, thereby increasing low density lipoprotein uptake. In wild-type mice, mAb1 increases hepatic low density lipoprotein receptor protein levels ca. 2fold and lowers total serum cholesterol by up to 36%
-
additional information
-
L-1-tosylamido-2-phenylethyl chloromethyl ketone; Nalpha-(p-tosyl)lysine chloromethyl ketone; not: 1,10-phenanthroline; trans-epoxysuccinate compounds
-
additional information
-
no inhibition with eglin c mutant Arg replaced with Asp at P3
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
atorvastatin
-
significantly increases circulating PCSK9 levels by 34% compared with baseline and placebo and decreases low density lipoprotein cholesterol levels by 42%
CT-peptide
-
increases PC1/3 activity at low concentrations (nanomol). PC1/3, through its various domains, is capable of controlling its enzymatic activity in all regions of the cell that it encounters. Activation of PC1/3 by 5 nanomol CT-peptide is the same in the presence or absence of propeptide
-
lovastatin
-
suppresses endogenous synthesis of sterols, increases both the proteins and mRNAs for PCSK9. 10 mM can reverse the increase of PCSK9 expression by lovastatin
sodium mevalonate
-
suppresses endogenous synthesis of sterols, PCSK9 is further increased
sterol-regulatory element binding protein-1
-
dramatically increases the promoter activity of PCSK9
-
sterol-regulatory element binding protein-2
-
dramatically increases the promoter activity of PCSK9
-
sterol-regulatory element binding protein-2
-
predominantly mediates sterol-dependent regulation of PCSK9 in vivo
-
additional information
-
depletion of sterols induces PCSK9 in a time-dependent manner
-
additional information
-
PCSK9 protein and mRNA are increased by refeeding after fasting. Supplementation with 2% cholesterol in the diet prevents the increase in PCSK9
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001
Ac-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide
-
pH 7.0, 37°C, in natural abundance H2O
0.023
benzyloxycarbonyl-Ala-Tyr-Lys-Lys 4-methylcoumarin 7-amide
-
pH 7.0, 21°C
0.001
D-Ac-Nle-Tyr-Lys-Arg 4-methylcoumarin 7-amide
-
pH 7.0, 37°C, in natural abundance H2O
additional information
additional information
-
analysis of binding kinetics data for PCSK9 with full-length low density lipoprotein receptor ectodomain, and isolated EGF-A repeat of low density lipoprotein receptor. The fast k-on and entropically driven thermodynamics observed for PCSK9-EGF-A binding stem from the functional replacement of water occupying stable PCSK9 hydration sites. The relatively fast k-off observed for EGF-A unbinding stems from the limited displacement of solvent occupying unstable hydration sites. Conversely, the slower k-off observed for EGF-A and low density lipoprotein receptor unbinding from mutant D374Y stems from the destabilizing effects of this mutation on PCSK9 hydration sites, with a concomitant increase in the persistence of the bound complex
-
additional information
additional information
binding affinities/association and dissociation constants of LDL receptor interaction with intact and cleaved enzyme, overview
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2640
benzyloxycarbonyl-Ala-Tyr-Lys-Lys 4-methylcoumarin 7-amide
-
pH 7.0, 21°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00000003
eglin c mutant Tyr replaced with Glu at P4
-
pH 7.5, 37°C
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00823
5alpha,6alpha-epoxy-(22E,24R)-ergosta-8(14),22-diene-3beta,7beta-diol
Homo sapiens
pH and temperature not specified in the publication
0.00718
hanabiratakelide A
Homo sapiens
pH and temperature not specified in the publication
additional information
additional information
Homo sapiens
at 20°C in 0.05 ml of buffer containing 10 mM Hepes, pH 7.4, 150 mM NaCl, 0.1 mM CaCl2, and 0.05% (w/v) bovine serum albumin: 0.0000048 mM with 1G08 fragment antigen binding, when wild-type expressed in HEK-293 cells, 0.0000150 mM with 1G08 fragment antigen binding, when wild-type expressed in Hep-G2 cells, 0.001 mM with 1G08 fragment antigen binding, when mutant R549A , mutant R580A/R582A and mutant E607A/K609A/E612N expressed in HEK-293 cells
-
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
brenda
cloned KEX2 gene introduced into the kex2 mutant cells and the KEX2 gene product expressed in these cells
-
-
brenda
yeast, strain X-2180, haploid cells
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
mild expression of PC1 and moderate expression of PC2. PC1 and PC2 in cerebral cortex colocalizes in pyramidal and non-pyramidal neurons with carboxypeptidase-E and somatostatin
brenda
-
weak expression of PC1 in CA1, CA2 and CA3 regions and nerve fibers. Moderate expression of PC2 in CA1, CA2 and CA3 regions and mild expression in nerve fibers. Colocalization of PC1 and PC2 with carboxypeptidase-E and somatostatin mostly selectively and preferentially in interneurons
brenda
-
brenda
additional information
in healthy volunteers, there is no significant difference in plasma PCSK9 measured between men and women
brenda
-
concentrations of PCSK9 in serum vary considerably from person to person
brenda
low gene expression level, gene expression but no enzyme protein content
brenda
-
low gene expression level, gene expression but no enzyme protein content
-
brenda
additional information
in LDL-receptor null mutant cells, gene expression and protein profiles, overview
brenda
additional information
-
in LDL-receptor null mutant cells, gene expression and protein profiles, overview
-
brenda
additional information
-
mild expression of PC1 and strong expression of PC2 in striatum. Colocalization of PC1 and PC2 with carboxypeptidase-E and somatostatin mostly selectively and preferentially in interneurons of the striatum
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
epithelial cells, accumulates at the apical and basolateral sides of the cells
brenda
secretion of the enzyme can be attenuated by annexin A2. Plasma concentration of the enzyme can be reduced by PPARalpha-dependent cleavage
-
brenda
the enzyme's prodomain inhibits intermolecular proteolysis in trans and requires the C-terminus for full inhibition and proper secretion, residue Val149 is critical for secretion
-
brenda
on its way through the Golgi and trans-Golgi complex, the enzyme co-localizes with the protein sortilin, the protein-protein interaction is probably required for cellular secretion
brenda
on its way through the Golgi and trans-Golgi complex, the enzyme co-localizes with the protein sortilin, in sortilin-knockout mice the plasma enzyme concentration is decreased, the protein-protein interaction is probably required for cellular secretion
brenda
additional information
residues of the prodomain C-terminus regulate proteolysis and secretion independently
-
brenda
additional information
the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage
-
brenda
additional information
the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage
-
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
malfunction
-
at t = 585 min, PCSK9-/- hepatocytes exhibit 90% less activity than wild-type
malfunction
cells with lower PCSK9 expression and secretion have a low density lipoprotein binding activity augmented by 200%
malfunction
-
in addition to its effect on LDL-cholesterol, PCSK9 deficiency may protect against cardiovascular disease by reducing postprandial triglyceridemia: PCSK9-deficient mice show a dramatically decreased postprandial triglyceridemia compared with their wild-type littermates. Intestinal triglyceride output is not quantitatively modified by PCSK9 deletion. PCSK9-/- mice present with a significant reduction of lymphatic apoB secretion compared to PCSK9+/+ mice. PCSK9-/- mice secrete larger triglyceride-rich lipoprotein than wild-type littermates. PCSK9-deficient mice have an increased ability to clear chylomicrons compared to wild-type littermates. The dramatic reduction of postprandial lipemia in PCSK9-/- mice results from the combination of various effects, including the intestinal secretion of larger chylomicrons, and their higher hepatic clearance rate
malfunction
D374Y is a naturally occurring gain-of-function mutation causing severe hypercholesterolaemia in humans due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant
malfunction
enzyme-knockout mice have more visceral adipose tissue. Enzyme-knockout mice carry more LDL receptor and less insulin in the pancreas, leading to hyperglycemia and glucose intolerance. beta-cell islets of enzyme-knockout mice inhibit signs of inflammation and apoptosis. This phenotype is modulated by gender and age
malfunction
gain-of-function mutations of the enzyme are associated with hypercholesterolemia and increased risk of cardiovascular events, while loss-of-function mutations cause low-plasma LDL-C levels and a reduction of cardiovascular risk without known unwanted effects on individual health. Inhibition of PCSK9 alone and in addition to statins potently reduces serum LDL-C concentrations. Mutations of the enzyme leading to reduced expression and or function are associated with a reduced rate of coronary heart disease, myocardial infarction and overall cardiovascular events, an effect being more pronounced in colored as compared to white subjects
malfunction
-
lack of PCSK6-dependent corin activation leads to hypertension. PCSK6-mediated processing of corin is reduced in the presence of corin variants T555I and Q568P previously associated to hypertension and to heart disease
metabolism
-
an interaction between the prodomain and C-terminal domain regulates the secretion of PCSK9
metabolism
PCSK6 can activate NF-kappaB, STAT3 and ERK1/2 signaling pathways in vitro to enhance cell proliferation, migration, invasion and inflammation in rheumatoid arthritis synovial fibroblast (RASF) cells. Recombinant enzyme rhPCSK6 promotes the production of pro-inflammatory factors in RASFs. Pro?inflammatory cytokines serve promixadnent roles in rheumatoid arthritis. RASFs can secrete interleukin (IL)-1alpha, IL-1beta, IL-6, IL-17, and TNF-alpha
physiological function
-
high level of activity in wild-type PCSK9+/+ hepatocytes. At t = 585 min, the activity of 20 microg of total hepatocyte lysates is 360% higher than that of 10 microg of purified protein
physiological function
PCSK9 binds to the low density lipoprotein receptor and leads to low density lipoprotein receptor degradation and inhibition of plasma low density lipoprotein cholesterol clearance. PCSK9 C-terminal domain contributes to its inhibition of low density lipoprotein receptor function mainly through its role in the cellular uptake of PCSK9 and low-density lipoprotein receptor complex
physiological function
PCSK9-induced upregulation of cholesterol biosynthesis genes results from intracellular cholesterol starvation. PCSK9 affects metabolic pathways beyond cholesterol metabolism in Hep-G2 cells. Pathways that are presumably regulated by PCSK9 and are independent of its effects on cholesterol uptake include protein ubiquitination, xenobiotic metabolism, cell cycle, and inflammation and stress response
physiological function
proprotein convertase subtilisin-kexin type 9 is a key regulator of low density lipoprotein receptor processing, and affects especially intermediate density lipoproteins. The enzyme pathway may affect plasma triglycerides via effects on the metabolism of triglyceriderich LDL particles
physiological function
-
proprotein convertase subtilisin/kexin 9 enhances the degradation of the LDL receptor in endosomes/lysosomes, resulting in increased circulating LDLc. The enzyme can also mediate the degradation of LDL receptor lacking its cytosolic tail, the transmembrane-domain of the receptor is not involved, but a lysosomal-targeting factor, overview. Role for the enzyme in enhancing tumor metastasis, consequences of enzyme inhibition for lowering LDLc and tumor metastasis
physiological function
proprotein convertase subtilisin/kexin 9 enhances the degradation of the LDL receptor in endosomes/lysosomes, resulting in increased circulating LDLc. The enzyme can also mediate the degradation of LDL receptor lacking its cytosolic tail, the transmembrane-domain of the receptor is not involved, but a lysosomal-targeting factor.overview. The LDL receptor is insensitive to the enzyme in murine B16F1 melanoma cells, but the enzyme is able to induce degradation of the low density lipoprotein receptor-related protein 1, suggesting distinct targeting mechanisms for these receptors. Role for the enzyme in enhancing tumor metastasis
physiological function
-
proprotein convertase subtilisin/kexin 9 enhances the degradation of the LDL receptor in endosomes/lysosomes, resulting in increased circulating LDLc. The enzyme is capable of acting upon the LDL receptor in CHO 13-5-1 cells lacking LRP-1. It also acts on LRP-1 in the absence of the LDL receptor in CHO-A7 cells, where re-introduction of the LDL receptor leads to reduced enzyme-mediated degradation of LRP-1
physiological function
proprotein convertase subtilisin/kexin 9 regulates plasma LDL cholesterol levels by regulating the degradation of LDL receptors, furin resistance is the underlying molecular mechanism for the gain of function phenotype
physiological function
proprotein convertase subtilisin/kexin type 9 negatively regulates the low-density lipoprotein (LDL) receptor in hepatocytes and plays an important role in controlling circulating levels of LDL-cholesterol. It interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor, resulting in results in increased secretion of apoB-containing lipoproteins and increased levels of cholesterol and triacylglycerol. PCSK9/apoB interaction results in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Role for the enzyme in shuttling between apoB and LDLR-receptor
physiological function
proprotein convertase subtilisin/kexin type 9 negatively regulates the low-density lipoprotein (LDL) receptor in hepatocytes and plays an important role in controlling circulating levels of LDL-cholesterol. It interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor, resulting in results in increased secretion of apoB-containing lipoproteins and increased levels of cholesterol and triacylglycerol. PCSK9/apoB interaction results in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Role for the enzyme in shuttling between apoB and LDLR-receptor
physiological function
residues of the prodomain C-terminus regulate proteolysis and secretion independently. The prodomain C-terminus regulates protein secretion but is not required for catalytic domain binding
physiological function
the enzyme binds to LDL-C receptors in hepatocytes promoting its autocatalytic cleavage. Regulation of PCSK9 gene expression by a number of transcription factors or cofactors, overview
physiological function
the enzyme is important for brain development, especially the cerebellum. The enzyme reduces the hepatic uptake of LDL-C by increasing the endosomal and lysosomal degradation of LDL receptors. The regulation of the enzyme, its molecular function in lipid homeostasis and the emerging evidence on the extra-hepatic effects of the enzyme. High enzyme concentrations downregulate LDLR expression and favor the formation of oxidized (ox)-LDL. Development of atherosclerosis involves endothelial cell apoptosis and accumulation of foam cells, both of which can be triggered by oxidized LDL-C (oxLDL-C). The enzyme binds to LDL-C receptors in hepatocytes promoting its autocatalytic cleavage. Regulation of PCSK9 gene expression by a number of transcription factors or cofactors, overview
physiological function
the enzyme promotes the degradation of the hepatic low density lipoprotein receptor. The C-terminal domain of the enzyme is unlikely to be involved in a direct extracellular interaction with the LDL-receptor
physiological function
proprotein convertase subtilisin/kexin type 6 promotes in vitro proliferation, migration and inflammatory cytokine secretion of synovial fibroblast-like cells from rheumatoid arthritis via nuclear-kappaB, signal transducer and activator of transcription 3 and activator of transcription 3 and extracellular signal regulated 1/2 pathways. rhPCSK6 induces activation of the ERK1/2, STAT3 and NF-kappaB signaling pathways
physiological function
recombinant PCSK6 significantly increases the proliferation, invasion and migraxadtion abilities of breast cancer MDA-MB-231 cells. In addition, PCSK6 treatment reduces cell cycle arrest and prevents apoptosis of MDA-MB-231 cells. PCSK6 treatment also increases the expression of phosphorylated extracellular signal-regulated kinase 1/2 and Wnt family member 3A, suggesting that these pathways are activated by PCSK6. Enzyme PCSK6 may promote the proliferation of breast cancer MDA-MB-231 cells by disturbing cell cycle arrest via the mitogen-activated protein kinase pathway
physiological function
-
the enzyme is involved in pro-atrial natriuretic peptide (pro-ANP) processing in the heart, key functions of PCSK6 are in the cardiovascular system to control blood pressure homeostasis
physiological function
-
proprotein convertase subtilisin/kexin type 9 negatively regulates the low-density lipoprotein (LDL) receptor in hepatocytes and plays an important role in controlling circulating levels of LDL-cholesterol. It interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor, resulting in results in increased secretion of apoB-containing lipoproteins and increased levels of cholesterol and triacylglycerol. PCSK9/apoB interaction results in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Role for the enzyme in shuttling between apoB and LDLR-receptor
-
additional information
differential structural requirements of the proteolytic site and requirements for secretion in trans in a system that effectively bypasses the need for proteolysis, overview. The enzyme's prodomain inhibits intermolecular proteolysis in trans and requires the C-terminus for full inhibition and proper secretion. the enzyme's active site and its adjacent residues serve as an allosteric modulator of protein secretion independent of its role in proteolysis, specific residues in the protease recognition sequence can differentially modulate the effects on proteolysis and secretion
additional information
mutations in the EGF-A binding domain of the LDL receptor associated with familiar hypercholesterolemia increases enzyme PCSK9 binding. The formed PCSK9-LDL receptor complex is internalized again by clathrin-mediated endocytosis and the complex is then routed to the sorting endosome/lysosome. At acidic pH of the endosome/lysosome, an additional interaction between the ligand-binding domain of the LDL receptor and the C-terminal enzyme domain occurs and the enzyme remains bound to the LDL receptor, which fails to adopt a closed conformation which is required for LDL receptor recycling, mechanism, overview
additional information
the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain. Areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor, Equilibrium binding parameters for the interaction between the LDL-R ectodomain and wt PCSK9 as well as PCSK9 mutants determined by surface plasmon resonance at 25°C, steady-state analysis and kinetic analysis, overview
additional information
-
the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain. Areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor, Equilibrium binding parameters for the interaction between the LDL-R ectodomain and wt PCSK9 as well as PCSK9 mutants determined by surface plasmon resonance at 25°C, steady-state analysis and kinetic analysis, overview
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). KEX2_CANAW
Candida albicans (strain WO-1)
938
1
105144
Swiss-Prot
Secretory Pathway (Reliability: 1)
KEX2_YEAST
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
814
1
90003
Swiss-Prot
Secretory Pathway (Reliability: 2)
K0KH55_WICCF
Wickerhamomyces ciferrii (strain ATCC 14091 / BCRC 22168 / CBS 111 / JCM 3599 / NBRC 0793 / NRRL Y-1031 F-60-10)
812
1
90782
TrEMBL
Secretory Pathway (Reliability: 2)
B8LXM9_TALSN
Talaromyces stipitatus (strain ATCC 10500 / CBS 375.48 / QM 6759 / NRRL 1006)
823
1
90466
TrEMBL
Secretory Pathway (Reliability: 1)
A0A5K1K067_9APHY
344
0
38705
TrEMBL
other Location (Reliability: 2)
A0A5K1K678_9APHY
105
0
11758
TrEMBL
other Location (Reliability: 2)
Q4WQI8_ASPFU
Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100)
844
1
92361
TrEMBL
Secretory Pathway (Reliability: 3)
A2Q9N6_ASPNC
Aspergillus niger (strain CBS 513.88 / FGSC A1513)
844
1
92449
TrEMBL
Secretory Pathway (Reliability: 4)
G3XT78_ASPNA
Aspergillus niger (strain ATCC 1015 / CBS 113.46 / FGSC A1144 / LSHB Ac4 / NCTC 3858a / NRRL 328 / USDA 3528.7)
844
1
92449
TrEMBL
Secretory Pathway (Reliability: 4)
A0A075FQ13_9EURY
1257
1
136821
TrEMBL
-
B2J322_NOSP7
Nostoc punctiforme (strain ATCC 29133 / PCC 73102)
662
0
71744
TrEMBL
-
A0A0F4YH34_TALEM
839
1
92127
TrEMBL
Secretory Pathway (Reliability: 1)
B9W8S2_CANDC
Candida dubliniensis (strain CD36 / ATCC MYA-646 / CBS 7987 / NCPF 3949 / NRRL Y-17841)
953
1
107015
TrEMBL
Secretory Pathway (Reliability: 1)
A0A8J8VY43_9EURO
835
1
91629
TrEMBL
Secretory Pathway (Reliability: 2)
A0A5K1K3P5_9APHY
55
0
6023
TrEMBL
other Location (Reliability: 3)
A0A5K1K3N5_9APHY
377
0
44167
TrEMBL
other Location (Reliability: 1)
Q9UUZ5_ASPNG
844
1
92491
TrEMBL
Secretory Pathway (Reliability: 4)
A0A073CH67_PLAAG
729
0
79287
TrEMBL
-
PCSK6_HUMAN
969
0
106420
Swiss-Prot
Chloroplast (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
68000
-
x * 87000, PC1, SDS-PAGE. x * 75000, proPC2, SDS-PAGE. x * 68000, mature PC2, SDS-PAGE
75000
-
x * 87000, PC1, SDS-PAGE. x * 75000, proPC2, SDS-PAGE. x * 68000, mature PC2, SDS-PAGE
75979
1 * 75979, purified PCSK9, gel filtration. 1* 45708, purified PCSK9DELTAC, gel filtration
87000
-
x * 87000, PC1, SDS-PAGE. x * 75000, proPC2, SDS-PAGE. x * 68000, mature PC2, SDS-PAGE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 87000, PC1, SDS-PAGE. x * 75000, proPC2, SDS-PAGE. x * 68000, mature PC2, SDS-PAGE
monomer
additional information
monomer
1 * 75979, purified PCSK9, gel filtration. 1* 45708, purified PCSK9DELTAC, gel filtration
additional information
the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain
additional information
-
the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
-
mutation of N-glycosylation site N146 results in the decreased zymogen activation of proPC1/3 and virtually inhibits its secretion. Mutation of glycosylation site N618A mutation does not significantly affect zymogen activation. The presence, but not the exact structure, of N-glycans is crucial for proPC1/3 zymogen processing
proteolytic modification
proteolytic modification
autocatalytic processing of the single-chain enzyme precursor in the endoplasmic reticulum is required for enzyme activation. Ca2+-dependent enzyme-processing activities of hepsin and furin. Proprotein convertase furin cleaves the enzyme at Arg218-Gln219 in the surface-exposed 218 loop, furin cleavage sequence is 215RFHRQ219. The serine protease hepsin cleaves PCSK9 at the furin cleavage site. The furin-cleaved form circulates in blood along with the intact form, albeit at lower concentrations, and is no longer able to degrade LDL receptor attributed to the loss of the N-segment, as well as the prodomain from PCSK9. neutralizing anti-hepsin antibody Ab25 completely inhibits enzyme cleavage. Enzyme domains and protease cleavage sites, overview
proteolytic modification
conversion of wild-type proPCSK9 to mature PCSK9 occurs in an intramolecular fashion, but the prodomain and catalytic domain can be assembled in trans (i.e. as two separate polypeptides), which effectively bypasses the need for proteolysis and does not require intrinsic proteolytic activity
proteolytic modification
the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage
proteolytic modification
the pro-form of the enzyme is synthesized in the endoplasmic reticulum. The binding of pro-PCSK9 to the low-density lipoprotein receptor in the endoplasmic reticulum supports the transport of the low-density lipoprotein receptor towards the Golgi complex. Trafficking of the pro-enzyme to the Golgi apparatus depends on the presence of the protein Sec24A. Within the Golgi, the pro-domain of the pro-enzyme is autocatalytically cleaved off, but remains non-covalently bound to the mature enzyme assisting the folding of the enzyme, and blocking its catalytic activity. Binding of pro-enzyme to the precursor form of the low-density lipoprotein receptor promotes PCSK9 autocatalytic cleavage
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystallized by hanging drop method, in complex with an Ala-Lys-Arg boronic acid inhibitor, space group P6(5)22, a = b = 113.8 A, c = 370.2 A
in complex with Ac-Arg-Glu-Lys-Arg-peptidyl boronic acid inhibitor
-
Kex2 in complex with the Ac-R-E-R-K-chloromethylketone, containing a noncognate lysine at the P1 position. Secondary subsite in the S1 pocket is present, which recognizes and binds the P1 lysine in a more shallow fashion than arginine. Kex2 contains well defined subsites that have optimally arranged electrostatic charge that positions correct substrates for hydrolysis. Chemical nature of the peptidyl inhibitor has little effect on ligand positioning at the active site in the alkylated enzyme forms
-
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A443T
-
is expressed, processed, and secreted normally, and reduces cellular LDL uptake in a concentration-dependent like the wild-type
C678X
a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum
D374Y
DeltaN218
-
in COS-1 cells only apparent upon co-expression of PC5A. Untreated Y1 cells secrete PCSK9-DeltaN218, stimulation with 8-Br-cAMP increases the level and especially that of the 34-kDa PCSK9 product
E569K
site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
E607A/K609A/E612N
mutation does not affect the overall integrity of the PCSK9 protein, shows similar cellular uptake potencies as the wild-type, impairs 1G08-PCSK9 binding
F216L
G517R
site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
N425S
-
is expressed, processed, and secreted normally, and reduces cellular LDL uptake in a concentration-dependent like the wild-type
Q152H
a dominant negative mutation that restricts enzyme proteolysis and secretion independently
Q152I
te mutation completely abrogates proteolysis in both intra- and intermolecular systems but has only a limited impact on secretion
R215H
a naturally occurring gain-of-function mutation associated with hypercholesterolemia, the mutation impairs furin-mediated enzyme cleavage
R218S
R469W
-
natural mutation, cannot modify the ability of PC5A to produce the 34-kDa PCSK9 product in HEK293 cells
R496W
-
natural mutation, cannot modify the ability of PC5A to produce the 34-kDa PCSK9 product in HEK293 cells
R549A
mutation does not affect the overall integrity of the PCSK9 protein, shows similar cellular uptake potencies as the wild-type, impairs 1G08-PCSK9 binding
R580A/R582A
mutation does not affect the overall integrity of the PCSK9 protein, shows similar cellular uptake potencies as the wild-type, impairs 1G08-PCSK9 binding
R659A
site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
R659E
site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
S127R
S386A
S462P
a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum
S636R
site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
V149A
the mutant shows intolerance for intermolecular cleavage of the enzyme, residue Val149 is critical for secretion
V610R
site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
V644R
site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
C678X
a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum
N146A
-
mutation results in the decreased zymogen activation of proPC1/3 and virtually inhibits its secretion
N374A
-
mutant is processed and secreted at nearly the same rate and with the same apparent molecular mass as wild-type. Residue N374 does not appear to bear an N-glycan
S462P
a loss-of-function mutation that abolishes the release of the enzyme from the endoplasmic reticulum
D176G/D210A/D211S
-
no preference for positively charged residues at P2 position, and S2 pocket is more solvent accessible, leading to preference for MR- over LR- or FR-containing substrates
E255I
-
significantly decreased recognition of P4Arg residue in a tetrapeptide substrate
T252D
-
increased recognition of Arg in P4 position, 14fold higher kcat/KM ratio for Arg than for Ala at position P6
T252D/Q283E
-
increased recognition of Arg in P4 position, 15fold higher kcat/KM ratio for Arg than for Ala at position P6
additional information
D374Y
gain-of-function mutant, human monoclonal antibody mAb1 also blocks binding of PCSK9 to low density lipoprotein receptor in the mutant
D374Y
gain-of-function PCSK9, has a greater activity reducing low density lipoprotein receptor in Hep-G2 cells
D374Y
naturally occurring gain-of-function mutation, associated to hypercholesterolemia and premature atherosclerosisias. Has less effect on processing (49% maturation)
D374Y
-
mutant kinetic data show a slower k-off for substrate domain EGF-A and full-length low density lipoprotein receptor unbinding which stems from the destabilizing effects of this mutation on PCSK9 hydration sites, with a concomitant increase in the persistence of the bound complex
D374Y
-
naturally occurring gain-of-function mutant causes severe hypercholesterolemia
D374Y
a naturally occurring gain-of-function mutation causing severe hypercholesterolaemia in humans due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant
F216L
naturally occurring gain-of-function mutation, associated to hypercholesterolemia and premature atherosclerosisias. Is matured to the same extent than the wild type (67% maturation)
F216L
a naturally occurring gain-of-function mutation associated with hypercholesterolemia, the mutation impairs furin-mediated enzyme cleavage
R218S
a naturally occurring gain-of-function mutation associated with hypercholesterolemia, the mutation impairs furin-mediated enzyme cleavage
S127R
naturally occurring gain-of-function mutation, associated to hypercholesterolemia and premature atherosclerosisias. Strongly diminishes processing (21% maturation)
S127R
-
naturally occurring gain-of-function mutant causes severe hypercholesterolemia
S386A
catalytically inactive, strongly diminishes processing (8% maturation)
additional information
-
splicing variant of PCSK9 with an in-frame deletion of the eighth exon of 58 amino acids. Expressed in multiple tissues, including liver, small intestine, prostate, uterus, brain, and adipose tissue. Unlike wild-type PCSK9, which is secreted, the splicing variant expressed in HEK-293 cells fails to process the prosegment intracellularly and thus is not secreted into the medium. Splicing variant does not change the LDLR protein levels
additional information
1G08 fragment antigen binding fails to bind a truncated form of PCSK9 lacking the C-terminal domain. Lack of the C-terminal domain compromises the ability of PCSK9 to internalize into cells, and to inhibit low density lipoprotein uptake
additional information
-
deletion of prodomain residues 31-40, 41-50, or 51-60 does not affect the self-cleavage, secretion, or LDLR-degrading activity of PCSK9, whereas deletion of residues 61-70 abolishes all of these functions. Deletion of the entire C-terminal domain does not impair PCSK9 self-cleavage or secretion but completely abolishes LDLR-degrading activity. Deletion of any one or two of the C-terminal domain modules does not affect self-cleavage but influences secretion and LDLR-reducing activity. In cotransfection experiments, a secretion-defective prodomain deletion mutant is efficiently secreted in the presence of C-terminal domain deletion mutants due to the transfer of the prodomain from the cotransfected C-terminal domain mutant to the prodomain mutant
additional information
a secretion-defective PCSK9 mutant can transfer its prodomain to a prodomain-deficient (and also secretion-defective) enzyme, rescuing the secretion of the latter enzyme species
additional information
analysis of the importance of the enzyme's C-terminus in degradation of the LDL-receptor by designing seven de novomutants of PCSK9 that fill potential druggable cavities
additional information
-
analysis of the importance of the enzyme's C-terminus in degradation of the LDL-receptor by designing seven de novomutants of PCSK9 that fill potential druggable cavities
additional information
-
Deltakex2 strongly enhances the cell fusion defect of Prm1-deficient mating pairs and causes a mild fusion defect in otherwise wild-type mating pairs. Deltakex2 and Deltakex1 fusion defects are suppressed by osmotic support. MATalpha/Deltakex2/Deltaprm1 mutant is sterile. A MATa/Deltakex2/Deltaprm1 mutant mates efficiently to a wild-type partner but poorly to a Deltaprm1 partner. Loss of KEX2 in the MATa partner alone decreases fusion by 15% compared with wild-type. Deltakex2 mutation produces a much stronger effect when placed in trans rather than in cis to the Deltaprm1 mutation. Severe cell wall defects in Deltakex2 mutant cells. Deltakex2 mutants produce cytoplasmic blebs embedded in the cell wall
additional information
-
PC1/3-deficient mice show severely impaired processing to GIP
additional information
-
deficiency of Kex2p endopeptidase completely removes K2 killing ability. Deficiency in Kex2p protease compromises the protein-dependent immunity function, and Deltakex2 transformants fail to display full resistance. They are sensitive to K2 toxins produced by wild-type K2 killer strains and only resistant to their own toxin
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7
-
37°C, t1/2: 250 min in Bis-Tris-HCl buffer, 6 min in Na-HEPES buffer
29424
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by Ni-nitriloacetic acid and size-exclusion chromatography, more than 95% pure
-
recombinant His-tagged enzyme from HEK-293T cell medium by nickel affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNAs encoding full-length PCSK9 splicing variant or mutants inserted into a modified pJB02 vector with a C-terminal Flag-HIS6 or HIS6 tag, respectively. The resulting constructs used for transient transfection of HEK-293 cells
-
cloned KEX2 gene introduced into the kex2 mutant cells and the KEX2 gene product expressed in these cells
-
expression in HEK293T and HepG2 cells
full-length and mutant PCSK9-V5-His proteins expressed in HEK-293 cells. Truncated PCSK9DELTAC (Gln-31-Ala-451) proteins with a C-terminal His tag expressed in Escherichia coli BL21 cells
recombinant His-tagged enzyme catalytic domain expression in HEK-293T cells and secretion to the medium
recombinant overexpression of the human enzyme in mouse LDL-receptor null mutant cells, expression and protein profiles, overview. Overexpression of PCSK9 increases plasma ApoB levels in an LDLR-independent fashion
recombinant PC1/3 produced using the baculovirus expression system in Sf-9 insect cells or through intracoelemic injection in insect larvae
-
transformation of the single-gene deletion strain Deltakex2 with pYEX12 plasmid
-
wild-type PCSK9 with a V5 epitope flag inserted into pcDNA3.1. PCSK9 mutants expressed in primary hepatocytes derived from PCSK9-/- mice
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
amounts of PCSK9 mRNA and protein in Caco-2/15 cells are associated to the regulation of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein-2 that can transcriptionally activate PCSK9 via sterol-regulatory elements located in its proximal promoter region. Depletion of cholesterol content by hydroxypropyl-beta-cyclodextrin upregulates PCSK9 transcripts (20%) and protein mass (540%), in parallel with sterol regulatory element binding protein-2 protein levels
cholesterol (0.1 mM) solubilized in albumin or micelles significantly downregulates PCSK9 gene (30%) and protein expression (50%) in Caco-2/15 cells. Cells treated with 25-hydroxycholesterol (0.05 mM) also display significant reduction in PCSK9 gene (37%) and protein (75%) expression. Addition of bile acids taurocholate and deoxycholate to the apical culture medium lowers PCSK9 gene expression (25%) and raises PCSK9 protein expression (30%), respectively, probably via the modulation of farnesoid X receptor
cholesteryl ester transfer protein inhibitors downregulate PCSK9 and LDLR expression through decreases in SREBP2 expression in hepatocytes. Glitazones, rapamycine, berberine, and resistin cause a reduction of enzyme expression via HNF1alpha reduction. Reduction of enzyme expression can be achieved by peroxisome proliferator-activated receptor alpha and activation of sterolresponse element binding protein 2. In HepG2 cells, hyperinsulinemia decreases the enzyme expression, an effect which is also observed in post-menopausal obese women
in healthy men 24 h hyperinsulinemia does not alter plasma the enzyme concentrations, and the enzyme expression is similar in normal, pre- and Typ2-diabetic patients
knockdown of PCSK9 expression in immortalized human hepatocytes using specific siRNA which results in a 38% and 53% decrease in PCSK9 protein quantity, respectively in cell lysates and culture media compared with controls
PCSK9 is expressed throughout the entire small intestine and in enterocytes. PCSK9 is expressed almost exclusively in the epithelial barrier of the duodenum and ileum, both in enterocytes and goblet cells. PCSK9 is 160% upregulated by 0.01 mM pravastatin in CaCo-2 cells after exposure for 48 h
PCSK9 is expressed throughout the small intestine and colon, at a level which does not vary significantly along the intestinal cephalo-caudal axis, and which is similar to that in the liver
-
PCSK9 levels correlate with plasma cholesterol, LDL-C, triglycerides, fasting glucose, age and body mass index. In hypercholesterolemic patients, circulating PCSK9 is higher than in healthy volunteers, and increases with increasing statin dose, and further increased when ezetimibe is added. Ezetimibe treatment of Hep-G2 (hepatocytes) and Caco-2 (enterocytes) cells causes a slight increase in PCSK9 mRNA, but no significant rise in PCSK9 protein secretion, suggesting that these transformed cells are not ideal model cell lines
the enzyme is up-regulated during apoptosis of neurons. Statins and increase the transcription factor SREBP2, statins also the HNF1alpha expression, and fibrates increase PPAralpha, all leading to increased enzyme PCSK9 expression. Activation of enzyme expression can be mediated by activation of insulin receptors and subsequent activation of the sterolresponse element binding protein 1 and mammalian target of rapamycin pathways
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
degradation
diagnostics
plasma enzyme concentrations are predictive for 4-5 year major cardiovascular event rate, and enzyme serum concentrations correlate with cardiovascular risk
drug development
medicine
molecular biology
-
role of Kex2 during cell fusion. Kex2 may promote cell fusion by proteolytically processing substrates that act in parallel to Prm1 as an alternative fusion machine, as cell wall components, or both
additional information
degradation
-
ASP preferentially cleaves the peptide bond following two basic residues, one of which is Lys, but not the bond following a single basic residue. Tertiary structure around the catalytic domain of ASP resembles, but is not identical to that of furin
degradation
-
Dpy-5 procollagen requires processing by BLI-4 for normal cuticle production
degradation
-
PC1/3 is essential and sufficient for the production of the intestinal incretin hormone GIP
drug development
-
anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia
drug development
-
anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia
drug development
anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia
drug development
PCSK9 is a highly promising therapeutic target to lower low density lipoprotein-cholesterol and therefore prevent or reduce atherosclerosis
drug development
the enzyme is a target for to drug development for inhibiting the PCSK9 processing pathway and ultimately disrupt the interaction with the LDL receptor, strategy for intracellular enzyme inhibition
drug development
-
PCSK6 may become a reasonable target for the development of drugs able to control high blood pressure by directly modulating pro-ANP cleavage
medicine
-
antisense inhibition of PCSK9 is an attractive and novel therapeutic approach for treating hypercholesterolemia
medicine
-
circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations. PCSK9 is likely not associated with specific lipoprotein particles. Assay providing a means to tailor PCSK9-inhibitor therapy to patients most likely to respond to and benefit from pharmacologic inhibition of PCSK9
medicine
-
PCSK9 is an attractive drug target for decreasing low density lipoprotein cholesterol levels. Addition of a PCSK9 inhibitor to statin therapy may result in even further low density lipoprotein cholesterol level decreases
medicine
-
a discrete C-terminal protein fragment competes with full-length PCSK9 for binding to LDLR in vitro and attenuates PCSK9-mediated hypercholesterolemia in mice
medicine
biologic-based strategies to inhibit proprotein convertase subtilisin/kexin type 9 show promise as anti-hypercholesterolemic and, therefore, anti-atherosclerotic therapies
medicine
the enzyme is a prominent therapeutic target for reducing LDL-cholesterol
medicine
the proprotein convertase subtilisin/kexin type 9 has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovascular diseases
medicine
the proprotein convertase subtilisin/kexin type 9 has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovascular diseases
medicine
-
PCSK6 may become a reasonable target for the development of drugs able to control high blood pressure by directly modulating pro-ANP cleavage and, therefore, increasing endogenous circulating alphaANP levels. Such a therapeutic approach may reveal beneficial also in the treatment of heart failure
medicine
-
antisense inhibition of PCSK9 is an attractive and novel therapeutic approach for treating hypercholesterolemia
-
additional information
-
expression of PCSK9 is regulated by sterol at the transcriptional level in HepG2 cells and that both SREBP-1 and SREBP-2 can transcriptionally activate PCSK9 via sterol-regulatory element in its proximal promoter region in vitro
additional information
-
requirement of both Kex1p and Kex2p peptidases for functional K2 toxin production
additional information
1G08 fragment antigen binding represents a useful new tool for delineating the mechanism of PCSK9 uptake and low density lipoprotein receptor degradation
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ORGANISM (UNIPROT)
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Direct measurement of acylenzyme hydrolysis demonstrates rate-limiting deacylation in cleavage of physiological sequences by the processing protease Kex2
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40
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Saccharomyces cerevisiae
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42
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2003
Saccharomyces cerevisiae (P13134)
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Specific cleavage of hybrid proteins by proteinase encoded by the KEX2 gene
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62
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1997
Saccharomyces cerevisiae
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32
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Saccharomyces cerevisiae
-
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Two engineered eglin c mutants potently and selectively inhibiting kexin or furin
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556
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Differential utilization of enzyme-substrate interactions for acylation but not deacylation during the catalytic cycle of Kex2 protease
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276
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brenda
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337
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Saccharomyces cerevisiae
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43
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579
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279
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281
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274
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283
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brenda
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53
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Saccharomyces cerevisiae
-
brenda
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176
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brenda
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63
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49
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104
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Saccharomyces cerevisiae
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296
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Homo sapiens (Q8NBP7)
brenda
Le May, C.; Kourimate, S.; Langhi, C.; Chetiveaux, M.; Jarry, A.; Comera, C.; Collet, X.; Kuipers, F.; Krempf, M.; Cariou, B.; Costet, P.
Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia
Arterioscler. Thromb. Vasc. Biol.
29
684-690
2009
Mus musculus, Homo sapiens (Q8NBP7), Homo sapiens
brenda
Kourimate, S.; Chetiveaux, M.; Jarnoux, A.L.; Lalanne, F.; Costet, P.
Cellular and secreted pro-protein convertase subtilisin/kexin type 9 catalytic activity in hepatocytes
Atherosclerosis
206
134-140
2009
Homo sapiens (Q8NBP7), Homo sapiens, Mus musculus
brenda
Ni, Y.G.; Condra, J.H.; Orsatti, L.; Shen, X.; Di Marco, S.; Pandit, S.; Bottomley, M.J.; Ruggeri, L.; Cummings, R.T.; Cubbon, R.M.; Santoro, J.C.; Ehrhardt, A.; Lewis, D.; Fisher, T.S.; Ha, S.; Njimoluh, L.; Wood, D.D.; Hammond, H.A.; Wisniewski, D.; Volpari, C.; Noto, A.; Lo Surdo, P.; Hubbard, B.; Carfi, A.
A proprotein convertase subtilisin-like/kexin type 9 (PCSK9) C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptake
J. Biol. Chem.
285
12882-12891
2010
Homo sapiens (Q8NBP7)
brenda
Lan, H.; Pang, L.; Smith, M.M.; Levitan, D.; Ding, W.; Liu, L.; Shan, L.; Shah, V.V.; Laverty, M.; Arreaza, G.; Zhang, Q.; Murgolo, N.J.; Hernandez, M.; Greene, J.R.; Gustafson, E.L.; Bayne, M.L.; Davis, H.R.; Hedrick, J.A.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells
J. Cell. Physiol.
224
273-281
2010
Homo sapiens (Q8NBP7)
brenda
Chan, J.C.; Piper, D.E.; Cao, Q.; Liu, D.; King, C.; Wang, W.; Tang, J.; Liu, Q.; Higbee, J.; Xia, Z.; Di, Y.; Shetterly, S.; Arimura, Z.; Salomonis, H.; Romanow, W.G.; Thibault, S.T.; Zhang, R.; Cao, P.; Yang, X.P.; Yu, T.; Lu, M.; Retter, M.W.; Kwon, G.; Henne, K.; Pan, O.; Tsai, M.M.; Fuchslocher, B.; Yang, E.; Z, Z.h.
A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates
Proc. Natl. Acad. Sci. USA
106
9820-9825
2009
Homo sapiens (Q8NBP7), Macaca fascicularis, Mus musculus
brenda
Davignon, J.; Dubuc, G.
Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels
Trans. Am. Clin. Climatol. Assoc.
120
163-173
2009
Homo sapiens (Q8NBP7), Homo sapiens
brenda
Mousavi, S.A.; Berge, K.E.; Berg, T.; Leren, T.P.
Affinity and kinetics of proprotein convertase subtilisin/kexin type 9 binding to low-density lipoprotein receptors on HepG2 cells
FEBS J.
278
2938-2950
2011
Homo sapiens
brenda
Zandberg, W.F.; Benjannet, S.; Hamelin, J.; Pinto, B.M.; Seidah, N.G.
N-glycosylation controls trafficking, zymogen activation and substrate processing of proprotein convertases PC1/3 and subtilisin kexin isozyme-1
Glycobiology
21
1290-1300
2011
Mus musculus
brenda
Du, F.; Hui, Y.; Zhang, M.; Linton, M.; Fazio, S.; Fan, D.
A novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9
J. Biol. Chem.
286
43054-43061
2011
Homo sapiens, Mus musculus
brenda
Pearlstein, R.; Hu, Q.; Zhou, J.; Yowe, D.; Levell, J.; Dale, B.; Kaushik, V.; Daniels, D.; Hanrahan, S.; Sherman, W.; Abel, R.
New hypotheses about the structure-function of proprotein convertase subtilisin/kexin type 9: Analysis of the epidermal growth factor-like repeat A docking site using WaterMap
Proteins
78
2571-2586
2010
Homo sapiens
brenda
Sun, H.; Samarghandi, A.; Zhang, N.; Yao, Z.; Xiong, M.; Teng, B.B.
Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor
Arterioscler. Thromb. Vasc. Biol.
32
1585-1595
2012
Homo sapiens (Q8NBP7), Mus musculus (Q80W65), Mus musculus C57BL/6 (Q80W65)
brenda
Schulz, R.; Schlueter, K.D.; Laufs, U.
Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9)
Basic Res. Cardiol.
110
4
2015
Mus musculus (Q80W65), Homo sapiens (Q8NBP7)
brenda
Kwakernaak, A.J.; Lambert, G.; Dullaart, R.P.
Plasma proprotein convertase subtilisin-kexin type 9 is predominantly related to intermediate density lipoproteins
Clin. Biochem.
47
679-682
2014
Homo sapiens (Q8NBP7)
brenda
Lipari, M.T.; Li, W.; Moran, P.; Kong-Beltran, M.; Sai, T.; Lai, J.; Lin, S.J.; Kolumam, G.; Zavala-Solorio, J.; Izrael-Tomasevic, A.; Arnott, D.; Wang, J.; Peterson, A.S.; Kirchhofer, D.
Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels
J. Biol. Chem.
287
43482-43491
2012
Homo sapiens (Q8NBP7)
brenda
Chorba, J.S.; Shokat, K.M.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) active site and cleavage sequence differentially regulate protein secretion from proteolysis
J. Biol. Chem.
289
29030-29043
2014
Homo sapiens (Q8NBP7)
brenda
Canuel, M.; Sun, X.; Asselin, M.C.; Paramithiotis, E.; Prat, A.; Seidah, N.G.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1)
PLoS ONE
8
e64145
2013
Cricetulus griseus, Homo sapiens, Mus musculus (Q80W65), Mus musculus
brenda
Geschwindner, S.; Andersson, G.M.; Beisel, H.G.; Breuer, S.; Hallberg, C.; Kihlberg, B.M.; Lindqvist, A.M.; OMahony, G.; Plowright, A.T.; Raubacher, F.; Knecht, W.
Characterisation of de novo mutations in the C-terminal domain of proprotein convertase subtilisin/kexin type 9
Protein Eng. Des. Sel.
2015
1-9
2015
Homo sapiens (Q8NBP7), Homo sapiens
brenda
Volpe, M.; Rubattu, S.
Novel insights into the mechanisms regulating pro-atrial natriuretic peptide cleavage in the heart and blood pressure regulation proprotein convertase subtilisin/kexin 6 is the corin activating enzyme
Circ. Res.
118
196-198
2016
Homo sapiens
brenda
Bang, S.; Chae, H.S.; Lee, C.; Choi, H.G.; Ryu, J.; Li, W.; Lee, H.; Jeong, G.S.; Chin, Y.W.; Shim, S.H.
New aromatic compounds from the fruiting body of Sparassis crispa (Wulf.) and their inhibitory activities on proprotein convertase subtilisin/kexin type 9 mRNA expression
J. Agric. Food Chem.
65
6152-6157
2017
Homo sapiens (Q8NBP7)
brenda
Jiang, H.; Wang, L.; Wang, F.; Pan, J.
Proprotein convertase subtilisin/kexin type 6 promotes in vitro proliferation, migration and inflammatory cytokine secretion of synovial fibroblast-like cells from rheumatoid arthritis via nuclear-kappaB, signal transducer and activator of transcription 3 and activator of transcription 3 and extracellular signal regulated 1/2 pathways
Mol. Med. Rep.
16
8477-8484
2017
Homo sapiens (P29122), Homo sapiens
brenda
Wang, P.; Wang, F.; Wang, L.; Pan, J.
Proprotein convertase subtilisin/kexin type 6 activates the extracellular signal-regulated kinase 1/2 and Wnt family member 3A pathways and promotes in vitro proliferation, migration and invasion of breast cancer MDA-MB-231 cells
Oncol. Lett.
16
145-150
2018
Homo sapiens (P29122), Homo sapiens
brenda
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