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A433T
is associated with a plasma PCSK9 concentration of 222 ng/ml
A443T
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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
DeltaN218
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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
G365R
is associated with a plasma PCSK9 concentration of 205 ng/ml
G517R
site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme
N425S
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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
Q152R
the mutation completely abolished both proteolysis and secretion
Q152X
four phenotypes of Q152X mutants, overview
Q190R
is associated with a plasma PCSK9 concentration of 55 ng/ml
R215H
a naturally occurring gain-of-function mutation associated with hypercholesterolemia, the mutation impairs furin-mediated enzyme cleavage
R434W
is associated with a plasma PCSK9 concentration of 51 ng/ml
R469W
-
natural mutation, cannot modify the ability of PC5A to produce the 34-kDa PCSK9 product in HEK293 cells
R46L
is associated with a plasma PCSK9 concentration of 51-59 ng/ml
R496W
-
natural mutation, cannot modify the ability of PC5A to produce the 34-kDa PCSK9 product in HEK293 cells
R53V
is associated with a plasma PCSK9 concentration of 39 ng/ml
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
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
N618A
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mutation does not significantly affect zymogen activation
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
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increased recognition of Arg in P4 position, 15fold higher kcat/KM ratio for Arg than for Ala at position P6
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
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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
-
noncleavable mutant
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
inactive mutant
S386A
catalytically inactive, strongly diminishes processing (8% maturation)
additional information
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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
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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
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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
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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
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PC1/3-deficient mice show severely impaired processing to GIP
additional information
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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