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Information on EC 3.4.21.B27 - proprotein convertase 7 and Organism(s) Homo sapiens and UniProt Accession Q16549
for references in articles please use BRENDA:EC3.4.21.B27preliminary BRENDA-supplied EC number
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3.4.21.B27 proprotein convertase 7Specify your search results
Word Map
- 3.4.21.B27
- furin
- tmprss6
- endoproteases
-
pcsks
- medicine
- pafah1b2
- hemochromatosis
-
furin-like
-
pnpla3
-
mbtps1
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
cleaves proteins typically at sites marked by the consensus Arg-Xaa-(Lys/Arg)-Arg sequence
Synonyms
pcsk7, proprotein convertase 7, proprotein convertase subtilisin/kexin type 7, subtilisin-like proprotein convertase 7, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CAS REGISTRY NUMBER
COMMENTARY
99676-46-7
-
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
Notch 1 + H2O
?
PC7 complements furin (EC 3.4.21.75) in cleaving Notch1 independently of PLC motif-mediated trans-Golgi network access
-
-
?
L-pyroglutamyl-Arg-Thr-Lys-Arg-4-methylcoumarin 7-amide + H2O
L-pyroglutamyl-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
-
-
-
?
Lys-Ser-Val-Lys-Lys-Arg-Ser-Val-Ser-Glu-Ile-Gln-Leu + H2O
Lys-Ser-Val-Lys-Lys-Arg + Ser-Val-Ser-Glu-Ile-Gln-Leu
-
-
-
-
?
pyro-ERTKR-7-amido-4-methylcoumarin + H2O
pyro-ERTKR + 7-amino-4-methylcoumarin
-
-
-
-
?
human transferrin receptor 1 + H2O
?
cleavage at an atypical site KTECER-/-LA
-
-
?
human transferrin receptor 1 + H2O
?
cleavage at an atypical site KTECER-/-LA, in which the P1 Arg100 and P6 Lys95 are critical,.cleavage at Arg100
-
-
?
human transferrin receptor 1 + H2O
?
cleavage at an atypical site KTECER-/-LA, in which the P1 Arg100 and P6 Lys95 are critical, cleavage at Arg100. Identification of the KTECER100;LA cleavage site by site-directed mutagenesis using substrate mutants, overview
-
-
?
additional information
?
-
hemojuvelin is not directly cleaved by the enzyme despite the presence of a RNRR motif. No activity on hepcidin
-
-
?
additional information
?
-
-
soluble proprotein convertase PC7 cannot process wild type epidermal growth factor precursor
-
-
?
additional information
?
-
-
the enzyme indirectly induces the processing of membrane-bound and soluble epidermal growth factor precursor into an about 115 kDa transmembrane form (EGF-115) at the VHPR290 motif. The production of EGF-115 is most probably achieved via the activation by PC7 of a latent serine and/or cysteine protease(s)
-
-
?
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
human transferrin receptor 1 + H2O
?
cleavage at an atypical site KTECER-/-LA
-
-
?
human transferrin receptor 1 + H2O
?
cleavage at an atypical site KTECER-/-LA, in which the P1 Arg100 and P6 Lys95 are critical,.cleavage at Arg100
-
-
?
additional information
?
-
hemojuvelin is not directly cleaved by the enzyme despite the presence of a RNRR motif. No activity on hepcidin
-
-
?
additional information
?
-
-
soluble proprotein convertase PC7 cannot process wild type epidermal growth factor precursor
-
-
?
additional information
?
-
-
the enzyme indirectly induces the processing of membrane-bound and soluble epidermal growth factor precursor into an about 115 kDa transmembrane form (EGF-115) at the VHPR290 motif. The production of EGF-115 is most probably achieved via the activation by PC7 of a latent serine and/or cysteine protease(s)
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
neoandrographolide
-
syn: 14-deoxyandrographiside, weak inhibitor, 50% inhibition between 0.5 mM and 2 mM
additional information
no or poor inhibition by decanoyl-RVKR-chloromethylketone
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001875
D-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.000081
D-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.00105
L-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.000312
L-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.0002
L-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.00012
L-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
correlation between plasma levels of the soluble human transferrin receptor 1 and the PCSK7 gene
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
complementary subcellular distribution of bioactive furin and proprotein convertase PC7. Furin activity in endosomes is 10fold less inhibited by decanoyl-RVKR-chloromethylketone and enriched over 3fold in endosomes compared to the trans-Golgi network. Development of targeted compartment-specific biosensors. Endogenous PC7, which resists the inhibitor, is active in distinct vesicles. Overexpressed PC7 cleaves trans-Golgi network/endosomal CLIP v.4 variants
-
-
active enzyme, proprotein convertase reaches the cell surface by a non-conventional secretory pathway through a brefeldin A- and COPII-coated vesicles independent way
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
four of nine conserved proprotein convertases (PCs), including furin, Pace4, PC5A/B, and PC7, cleave substrates after the minimal dibasic recognition motif (K/R)-(X)n-(K/R)Y, where n is 0, 2, 4, or 6 and X can be any amino acid. In 152 PC sequences examined across species, the catalytic sites are 95% identical
malfunction
metabolism
physiological function
malfunction
-
cells silenced for proprotein convertase 7 have substantially reduced MHC class I surface levels caused by high instability and significantly delayed surface accumulation of these molecules
physiological function
additional information
a PLC motif in the cytosolic tail of PC7 is dispensable for endosomal activity, but it is specifically required for trans-Golgi network recycling and to rescue proActivin-A cleavage in furin-depleted B16-F1 melanoma cells
malfunction
an enzyme PC7 chimera, in which the transmembrane domain and the cytosolic tail are replaced by that of the convertase furin, loses its ability to cleave the transferrin receptor
malfunction
the PLC motif in the cytosolic tail of proprotein convertase 7 (PC7) is dispensable for endosomal activity, but is specifically required for trans-Golgi network (TGN) recycling and to rescue proactivin-A cleavage in furin-depleted B16-F1 melanoma cells. In sharp contrast, PC7 complements furin in cleaving Notch1 independently of PLC-mediated TGN access
metabolism
when iron is limiting, human transferrin receptor TfR1 levels increase at least in part by way of the down-regulation of PC7 enzyme expression
metabolism
all proprotein convertase (PC) activity detected in the trans-Golgi network/endosomal system of B16-F1 cells is mediated by furin, but not by endogenous PC7. Enzyme PC7 can rescue proActivin-A cleavage in furin-depleted B16-F1 melanoma cells
physiological function
the enzyme is involved in the regulation of systemic iron homeostasis via shedding of human transferrin receptor 1, TfR1, as its unique mechanism. Shedding of hTfR1 by the enzyme requires endocytosis into acidic clathrin-coated vesicles, enzyme transmembrane domain and cytosolic tail are critical for hTfR1 shedding in the endosomes
physiological function
the enzyme is involved in the regulation of systemic iron homeostasis via shedding of soluble human transferrin receptor 1, TfR1, as its unique mechanism. But the enzyme is not involved in hepcidin regulation by influencing solube hemojuvelin level
physiological function
CRISPR editing reveals that both furin and PC7 are functional in B16-F1 cells and able to substitute for each other during Notch1 and ADAM10 precursor processing
physiological function
-
proprotein convertase 7 is required for normal MHC class I surface levels in the context of a defective peptide-loading complex
physiological function
-
proprotein convertase PC7 enhances the activation of the epidermal growth factor receptor pathway through processing of the epidermal growth factor precursor
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). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
a PLC motif in the cytosolic tail of PC7 is dispensable for endosomal activity, but it is specifically required for trans-Golgi network recycling and to rescue proActivin-A cleavage in Furin-depleted B16-F1 melanoma cells
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
lipoprotein
the enzyme has palmitoylated cysteines, Cys699 and Cys704 within its C-terminus, these posttranslational modifications are not required for transferrin receptor 1 shedding
proteolytic modification
after autocleavage, proprotein convertases (PCs) exit the endoplasmatic reticulum. They remain bound to their inhibitory cleaved prosegments in latent form until arrival at the cell surface or, in the case of furin, in acidic endosomes, probably to avoid precocious activation or degradation of their substrates. Activated furin can then recycle from endosomes to the trans-Golgi network by binding to specific adaptors in the cytosol
glycoprotein
-
mature proprotein convertase 7 is partially sulfated, Cys699 and Cys704 are palmitoylated at its cytosolic tail. The enzyme also undergoes N-glycosylation
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C699A
site-directed mutagenesis, the mutant activity with substrate transferrin receptor 1 is unaltered compared to the wild-type enzyme
C704A
site-directed mutagenesis, the mutant activity with substrate transferrin receptor 1 is unaltered compared to the wild-type enzyme
D188G
site-directed mutagenesis, the autocatalytic processing of the PC7 zymogen is severely impaired leading to accumulation of the inactive pro-enzyme
R316C
site-directed mutagenesis, the autocatalytic processing of the PC7 zymogen is severely impaired leading to accumulation of the inactive pro-enzyme
additional information
additional information
generation of a frameshift fsL506P enzyme mutant. Construction of an enzyme PC7 chimera, in which the transmembrane domain and the cytosolic tail are replaced by that of the convertase furin, the mutant loses its ability to cleave the transferrin receptor. Identification of the KTECER100;LA cleavage site by site-directed mutagenesis
additional information
proprotein convertase PC7 can rescue proActivin-A cleavage in furin-depleted B16-F1 melanoma cells
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Mono Q HR column chromatography, HIC 6FF column chromatography, and Superdex 200 gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme expression of wild-type enzyme mutant enzymes in HuH-7 cells, also expression of the wild-type enzyme in Hep-G2 cells, HEK-293 cells, K-562 cells, CHO cells, and COS-1 cells, functional co-expression with the human transferrin receptor 1 substrate
the distribution of proprotein convertase (PC) activities at the tissue level are monitored by introduction of biosensor CLIP (cell-linked indicator of proteolysis). CLIP v.3 is suitable for ratiometric imaging without interference by FRET, whereas CLIP v.4 can be used as a FRET-based biosensor to quantify PC activities in specific intracellular vesicles, enzyme and CLIP expression in HEK-293T cells. Fusion to the cytosolic tail of PC7 directs CLIP v.4 to compartments that harbor furin activity, but not full-length proprotein convertase 7 (PC7). Overexpressed PC7 cleaves trans-Golgi network/endosomal CLIP v.4 variants
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
depletion of iron in the medium of hepatoma cell lines incubated with the iron chelator desferrioxamine results in the enzyme downregulation
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-hemochromatosis
medicine
-
plays a role in Alzheimer´s disease by participating in the non-amyloidogenic pathway through the activation of alpha-secretase, can also contribute to pro-parathyroid hormone activation, could participate in the activation of viral surface glycoproteins including the HIV gp160 type I glycoprotein, seems likely that perturbance of the levels of PC7 could lead to cancer of lymphatic tissues, could be important in cell proliferation
additional information
compartment-specific biosensors can be used to gain insight into the regulation of proprotein convertase (PC) trafficking and to map the tropism of PC-specific inhibitors
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Basak, A.; Cooper, S.; Roberge, A.G.; Banik, U.K.; Chretien, M.; Seidah, N.G.
Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters
Biochem. J.
338
107-113
1999
Homo sapiens
-
Seidah, N.G.; Chretien, M.
Proprotein convertase 7
Handbook of Proteolytic Enzymes (Barrett, A. J. , Rawlings, N. D. , Woessner, J. F. , Eds. ) Academic Press
2
1877-1880
2004
Gallus gallus, Homo sapiens, Mus musculus, Rattus norvegicus
-
Page, R.E.; Klein-Szanto, A.J.; Litwin, S.; Nicolas, E.; Al-Jumaily, R.; Alexander, P.; Godwin, A.K.; Ross, E.A.; Schilder, R.J.; Bassi, D.E.
Increased expression of the pro-protein convertase furin predicts decreased survival in ovarian cancer
Cell. Oncol.
29
289-299
2007
Homo sapiens
Fugere, M.; Appel, J.; Houghten, R.A.; Lindberg, I.; Day, R.
Short polybasic peptide sequences are potent inhibitors of PC5/6 and PC7: use of positional scanning-synthetic peptide combinatorial libraries as a tool for the optimization of inhibitory sequences
Mol. Pharmacol.
71
323-332
2007
Homo sapiens
Freyer, C.; Kilpatrick, L.M.; Salamonsen, L.A.; Nie, G.
Pro-protein convertases (PCs) other than PC6 are not tightly regulated for implantation in the human endometrium
Reproduction
133
1189-1197
2007
Homo sapiens (Q16549)
Rousselet, E.; Benjannet, S.; Hamelin, J.; Canuel, M.; Seidah, N.
The proprotein convertase PC7: Unique zymogen activation and trafficking pathways
J. Biol. Chem.
286
2728-2738
2011
Homo sapiens, Rattus norvegicus
Rousselet, E.; Benjannet, S.; Marcinkiewicz, E.; Asselin, M.; Lazure, C.; Seidah, N.
Proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor
J. Biol. Chem.
286
9185-9195
2011
Homo sapiens, Mus musculus
Leonhardt, R.; Fiegl, D.; Rufer, E.; Karger, A.; Bettin, B.; Knittler, M.
Post-endoplasmic reticulum rescue of unstable MHC class I requires proprotein convertase PC7
J. Immunol.
184
2985-2998
2010
Homo sapiens
Guillemot, J.; Canuel, M.; Essalmani, R.; Prat, A.; Seidah, N.G.
Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin
Hepatology
57
2514-2524
2013
Homo sapiens (Q16549)
Schwienbacher, C.; Serafin, A.; Zanon, A.; Pramstaller, P.; Pichler, I.; Hicks, A.
Involvement of proprotein convertase PCSK7 in the regulation of systemic iron homeostasis
Hepatology
58
1860-1861
2013
Homo sapiens (Q16549)
Ginefra, P.; Filippi, B.G.H.; Donovan, P.; Bessonnard, S.; Constam, D.B.
Compartment-specific biosensors reveal a complementary subcellular distribution of bioactive furin and PC7
Cell Rep.
22
2176-2189
2018
Homo sapiens (Q16549), Mus musculus (Q61139)
Pelucchi, S.; Galimberti, S.; Greni, F.; Rametta, R.; Mariani, R.; Pelloni, I.; Girelli, D.; Busti, F.; Ravasi, G.; Valsecchi, M.G.; Valenti, L.; Piperno, A.
Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis
J. Gastroenterol. Hepatol.
31
1342-1348
2016
Homo sapiens (Q16549), Homo sapiens
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