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| Description | PCSK4 is a member of the family of subtilisin-like proprotein convertase (PCs) that process protein at basic residues. This protein is produced in the inactive zymogen form and is activated by proteolytic removal of its prodomain in the N-terminal site. |
| Expression | PCSK4 is restricted to the reproductive tract and expressed primarily in testicular germ cells and sperm. Low levels of PCSK4 mRNA have also been detected in ovaries and the placenta. |
| Localisation | PCSK4 exact intracellular location has not yet been determined. |
| Function | PCSK4 cleaves synthetic peptide substrates after an Arg in a basic sequence context; most often after paired basic residues (K/R-X-K/R), to release mature proteins from their proproteins. PCSK4 substrates include growth factors (DEAF-1, proIGF2, proenkephalin, proNGF, proPACAP, HGFR), receptors (IGF-1R, HGFR), and members of the ADAM (a-disintegrin-and-metalloproteinase) family (ADAM-1, ADAM-2, ADAM-3, ADAM-5. The activation/inactivation of these substrates implicated directly the latter to the regulation of gonadal functions, sperm motility, and species specific reproduction. |
| Homology | The PCSK4 catalytic domain has a high percentage of homology with those of the other PCs: 70% between PCSK4 and Furin. |
| Proprotein convertases in health and disease. |
| Artenstein AW, Opal SM. |
| N Engl J Med. 2011 Dec 29;365(26):2507-18. doi: 10.1056/NEJMra1106700. (REVIEW) |
| PMID 22204726 |
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| Enzymic characterization in vitro of recombinant proprotein convertase PC4. |
| Basak A, Toure BB, Lazure C, Mbikay M, Chretien M, Seidah NG. |
| Biochem J. 1999 Oct 1;343 Pt 1:29-37. |
| PMID 10493908 |
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| In vitro elucidation of substrate specificity and bioassay of proprotein convertase 4 using intramolecularly quenched fluorogenic peptides. |
| Basak S, Chretien M, Mbikay M, Basak A. |
| Biochem J. 2004 Jun 1;380(Pt 2):505-14. |
| PMID 14972029 |
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| Proprotein convertases: "master switches" in the regulation of tumor growth and progression. |
| Bassi DE, Fu J, Lopez de Cicco R, Klein-Szanto AJ. |
| Mol Carcinog. 2005 Nov;44(3):151-61. (REVIEW) |
| PMID 16167351 |
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| Peptide-protein interactions suggest that acetylation of lysines 381 and 382 of p53 is important for positive coactivator 4-p53 interaction. |
| Debnath S, Chatterjee S, Arif M, Kundu TK, Roy S. |
| J Biol Chem. 2011 Jul 15;286(28):25076-87. doi: 10.1074/jbc.M110.205328. Epub 2011 May 17. |
| PMID 21586571 |
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| Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review. |
| Gyamera-Acheampong C, Mbikay M. |
| Hum Reprod Update. 2009 Mar-Apr;15(2):237-47. doi: 10.1093/humupd/dmn060. Epub 2008 Dec 24. (REVIEW) |
| PMID 19109312 |
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| The potential anti-tumorigenic and anti-metastatic side of the proprotein convertases inhibitors. |
| Lahlil R, Calvo F, Khatib AM. |
| Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):83-91. (REVIEW) |
| PMID 19149690 |
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| Role of pro-IGF-II processing by proprotein convertase 4 in human placental development. |
| Qiu Q, Basak A, Mbikay M, Tsang BK, Gruslin A. |
| Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11047-52. Epub 2005 Jul 22. |
| PMID 16040806 |
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| Proprotein convertases: lessons from knockouts. |
| Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM. |
| FASEB J. 2006 Oct;20(12):1954-63. (REVIEW) |
| PMID 17012247 |
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| The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. |
| Seidah NG, Sadr MS, Chretien M, Mbikay M. |
| J Biol Chem. 2013 Jul 26;288(30):21473-81. doi: 10.1074/jbc.R113.481549. Epub 2013 Jun 17. (REVIEW) |
| PMID 23775089 |
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| What lies ahead for the proprotein convertases? |
| Seidah NG. |
| Ann N Y Acad Sci. 2011 Mar;1220:149-61. doi: 10.1111/j.1749-6632.2010.05883.x. (REVIEW) |
| PMID 21388412 |
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| Alteration in the processing of the ACRBP/sp32 protein and sperm head/acrosome malformations in proprotein convertase 4 (PCSK4) null mice. |
| Tardif S, Guyonnet B, Cormier N, Cornwall GA. |
| Mol Hum Reprod. 2012 Jun;18(6):298-307. doi: 10.1093/molehr/gas009. Epub 2012 Feb 21. |
| PMID 22357636 |
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| Genetics of the first seven proprotein convertase enzymes in health and disease. |
| Turpeinen H, Ortutay Z, Pesu M. |
| Curr Genomics. 2013 Nov;14(7):453-67. doi: 10.2174/1389202911314050010. |
| PMID 24396277 |
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