PCSK6

Proprotein convertase subtilisin/kexin type 6
Identifiers
Symbols	PCSK6 ; PACE4; SPC4
External IDs	OMIM: 167405 MGI: 102897 HomoloGene: 20569 ChEMBL: 2951 GeneCards: PCSK6 Gene
Gene ontology Molecular function • endopeptidase activity • serine-type endopeptidase activity • heparin binding • nerve growth factor binding Cellular component • extracellular space • endoplasmic reticulum • Golgi lumen • cell surface • membrane • extracellular matrix Biological process • zygotic determination of anterior/posterior axis, embryo • determination of left/right symmetry • glycoprotein metabolic process • protein processing • peptide hormone processing • regulation of BMP signaling pathway • nerve growth factor processing • nerve growth factor production • secretion by cell • neurotrophin TRK receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5046	18553
Ensembl	ENSG00000140479	ENSMUSG00000030513
UniProt	P29122	F6XJP7
RefSeq (mRNA)	NM_001291309	NM_001291184
RefSeq (protein)	NP_001278238	NP_001278113
Location (UCSC)	Chr 15: 101.3 – 101.53 Mb	Chr 7: 65.86 – 66.05 Mb
PubMed search

Proprotein convertase subtilisin/kexin type 6 is an enzyme that in humans is encoded by the PCSK6 gene.^[1][2] PCSK6 is a protease that cleaves NODAL into an active form to help trigger the development of left/right (LR) asymmetry.^[3] It may also be involved in left and right handedness in humans.^[4][5][6]

Function

The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can cleave precursor protein at their paired basic amino acid processing sites. Some of its substrates are - transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. Alternatively spliced transcript variants encoding different isoforms have been identified.^[2]

PCSK6 also cleaves and activates corin, a serine protease that regulates sodium homeostasis and blood pressure.^[7]

Clinical significance

This gene is thought to play a role in tumor progression.^[2]

PCSK6 deficiency causes salt-sensitive hypertension in mice.^[7]

References

1. Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ (Jan 1992). "Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15". DNA Cell Biol 10 (10): 757–69. doi:10.1089/dna.1991.10.757. PMID 1741956.
2. "Entrez Gene: PCSK6 proprotein convertase subtilisin/kexin type 6".
3. Constam DB, Robertson EJ (May 1, 2000). "SPC4/PACE4 regulates a TGFbeta signaling network during axis formation.". Genes & Development 14 (9): 1146–55. doi:10.1101/gad.14.9.1146. PMC 316583. PMID 10809672.
4. Scerri TS, Brandler WM, Paracchini S, Morris AP, Ring SM, Richardson AJ, Talcott JB, Stein J, Monaco AP (Feb 1, 2011). "PCSK6 is associated with handedness in individuals with dyslexia.". Human Molecular Genetics 20 (3): 608–14. doi:10.1093/hmg/ddq475. PMC 3016905. PMID 21051773.
5. Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, Timpson NJ, St Pourcain B, Smith GD, Ring SM, Stein J, Monaco AP, Talcott JB, Fisher SE, Webber C, Paracchini S (September 2013). "Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.". PLOS Genetics 9 (9): e1003751. doi:10.1371/journal.pgen.1003751. PMC 3772043. PMID 24068947.
6. Shore R, Covill L, Pettigrew KA, Brandler WM, Diaz R, Xu Y, Tello JA, Talcott JB, Newbury DF, Stein J, Monaco AP, Paracchini S (March 16, 2016). "The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.". Human Molecular Genetics 25 (6). doi:10.1093/hmg/ddw047.
7. Chen S, Cao P, Dong N, Peng J, Zhang C, Wang H, Zhou T, Yang J, Zhang Y, Martelli EE, Naga Prasad SV, Miller RE, Malfait AM, Zhou Y, Wu Q (Sep 2015). "PCSK6-mediated corin activation is essential for normal blood pressure". Nature Medicine 21 (9): 1048–53. doi:10.1038/nm.3920. PMID 26259032.

Further reading

• Bassi DE, Mahloogi H, Klein-Szanto AJ (2000). "The proprotein convertases furin and PACE4 play a significant role in tumor progression". Mol. Carcinog. 28 (2): 63–9. doi:10.1002/1098-2744(200006)28:2<63::AID-MC1>3.0.CO;2-C. PMID 10900462.
• Moulard M, Decroly E (2001). "Maturation of HIV envelope glycoprotein precursors by cellular endoproteases". Biochim. Biophys. Acta 1469 (3): 121–32. doi:10.1016/S0304-4157(00)00014-9. PMID 11063880.
• Seidah NG, Prat A (2003). "Precursor convertases in the secretory pathway, cytosol and extracellular milieu". Essays Biochem. 38: 79–94. PMID 12463163.
• Tsuji A, Higashine K, Hine C, Mori K, Tamai Y, Nagamune H, Matsuda Y (1994). "Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms.". Biochem. Biophys. Res. Commun. 204 (3): 1381–2. doi:10.1006/bbrc.1994.2616. PMID 7980617.
• Tsuji A, Higashine K, Hine C, Mori K, Tamai Y, Nagamune H, Matsuda Y (1994). "Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms". Biochem. Biophys. Res. Commun. 200 (2): 943–50. doi:10.1006/bbrc.1994.1541. PMID 8179631.
• Vollenweider F, Benjannet S, Decroly E, Savaria D, Lazure C, Thomas G, Chrétien M, Seidah NG (1996). "Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases". Biochem. J. 314 (Pt 2): 521–32. PMC 1217081. PMID 8670066.
• Zhong M, Benjannet S, Lazure C, Munzer S, Seidah NG (1997). "Functional analysis of human PACE4-A and PACE4-C isoforms: identification of a new PACE4-CS isoform". FEBS Lett. 396 (1): 31–6. doi:10.1016/0014-5793(96)01059-9. PMID 8906861.
• Decroly E, Wouters S, Di Bello C, Lazure C, Ruysschaert JM, Seidah NG (1997). "Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines". J. Biol. Chem. 271 (48): 30442–50. doi:10.1074/jbc.271.48.30442. PMID 8940009.
• Inocencio NM, Sucic JF, Moehring JM, Spence MJ, Moehring TJ (1997). "Endoprotease activities other than furin and PACE4 with a role in processing of HIV-I gp160 glycoproteins in CHO-K1 cells". J. Biol. Chem. 272 (2): 1344–8. doi:10.1074/jbc.272.2.1344. PMID 8995442.
• Mori K, Kii S, Tsuji A, Nagahama M, Imamaki A, Hayashi K, Akamatsu T, Nagamune H, Matsuda Y (1997). "A novel human PACE4 isoform, PACE4E is an active processing protease containing a hydrophobic cluster at the carboxy terminus". J. Biochem. 121 (5): 941–8. doi:10.1093/oxfordjournals.jbchem.a021677. PMID 9192737.
• Tsuji A, Hine C, Tamai Y, Yonemoto K, Mori K, Yoshida S, Bando M, Sakai E, Mori K, Akamatsu T, Matsuda Y (1997). "Genomic organization and alternative splicing of human PACE4 (SPC4), kexin-like processing endoprotease". J. Biochem. 122 (2): 438–52. doi:10.1093/oxfordjournals.jbchem.a021772. PMID 9378725.
• Moulard M, Chaloin L, Canarelli S, Mabrouk K, Darbon H, Challoin L (1998). "Retroviral envelope glycoprotein processing: structural investigation of the cleavage site". Biochemistry 37 (13): 4510–7. doi:10.1021/bi972662f. PMID 9521771.
• Nagahama M, Taniguchi T, Hashimoto E, Imamaki A, Mori K, Tsuji A, Matsuda Y (1998). "Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4)". FEBS Lett. 434 (1–2): 155–9. doi:10.1016/S0014-5793(98)00970-3. PMID 9738469.
• Viale A, Ortola C, Hervieu G, Furuta M, Barbero P, Steiner DF, Seidah NG, Nahon JL (1999). "Cellular localization and role of prohormone convertases in the processing of pro-melanin concentrating hormone in mammals". J. Biol. Chem. 274 (10): 6536–45. doi:10.1074/jbc.274.10.6536. PMID 10037747.
• Mori K, Imamaki A, Nagata K, Yonetomi Y, Kiyokage-Yoshimoto R, Martin TJ, Gillespie MT, Nagahama M, Tsuji A, Matsuda Y (1999). "Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells". J. Biochem. 125 (3): 627–33. doi:10.1093/oxfordjournals.jbchem.a022329. PMID 10050053.
• Sucic JF, Moehring JM, Inocencio NM, Luchini JW, Moehring TJ (1999). "Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain". Biochem. J. 339 (3): 639–47. doi:10.1042/0264-6021:3390639. PMC 1220200. PMID 10215603.
• Tsuji A, Yoshida S, Hasegawa S, Bando M, Yoshida I, Koide S, Mori K, Matsuda Y (2000). "Human subtilisin-like proprotein convertase, PACE4 (SPC4) gene expression is highly regulated through E-box elements in HepG2 and GH4C1 cells". J. Biochem. 126 (3): 494–502. doi:10.1093/oxfordjournals.jbchem.a022478. PMID 10467164.