PCSK6 explained

Proprotein convertase subtilisin/kexin type 6 is an protease that in humans is encoded by the PCSK6 gene which is located in chromosome 15.^{[1] [2]} Pcsk6 is a calcium-dependent serine endoprotease that catalyzes the post-translational modification of precursor proteins from its ‘latent’ form to the cleaved ‘active’ form. Active Pcsk6 has been reported to process substrates such as transforming growth factor β,^[3] pro-albumin,^[4] von Willebrand factor,^[5] and corin.^[6] Clinically, Pcsk6 is suggested to play a role in left/right asymmetry,^[7] structural asymmetry of the brain,^[8] handedness,^{[9] [10] [11]} tumor progression,^[12] hemostasis, and cardiovascular diseases.^[13]

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, pro-albumin, von Willebrand factor, and corin. Alternatively spliced transcript variants encoding different isoforms have been identified.

Clinical significance

During development: Throughout development, the spatial and temporal expression of pcsk6 regulates embryogenesis by activating TGFβ related differentiation factors, which include BMP and Nodal.^[14] Elevated levels of Pcsk6 was detected in maternal decidual cells of the implantation site and the extraembryonic ectoderm.^[15] The regulation of proper gradient of Nodal and BMPs is crucial for gastrulation,^[16] proximal-distal axis,^[17] and establishment of left-right axis patterning.^[18]

Developmental Pcsk6 knockout studies found that mice embryos that lack Pcsk6 develop heterotaxia, left pulmonary isomerism, and/or craniofacial malformations due to disruption in specification of anterior-posterior and left-right axis that resulted from the dysregulation of Nodal and BMP signaling.

In humans, Pcsk6 VNTR polymorphism is associated with the structural asymmetry of the frontal and temporal lobe, and  degree of handedness.

Cardiovascular disease: Pcsk6 is increasing interest as indicator and factor of cardiovascular disease. Pcsk6 KO mice was shown to develop salt-sensitive hypertension due to failure of pro-corin activation crucial to atrial natriuretic peptide regulation of blood pressure. A hypertensive patient was found to have a G/A mutation on the PCSK6 gene that resulted in an Asp282Asn (D282N) substitution at the Pcsk6 catalytic domain, which in turn, hinders corin processing. In vascular remodeling, Pcsk6 was found to induce smooth muscle cell migration in response to PDGFB by activating MMP14. When Pcsk6 was knocked out, the intimal hyperplasia response to in vivo carotid ligation was lowered.

Other: This gene is thought to play a role in tumor progression.

Further reading

• Shore R, Covill L, Pettigrew KA, Diaz R, Xu Y, Tello J, Talcott J, Newbury D, Stein J, Monaco A . The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts . Hum Mol Genet . 25 . 9 . 1771–1779 . 2016 . 26908617 . 4986331 . 10.1093/hmg/ddw047 .
• Bassi DE, Mahloogi H, Klein-Szanto AJ . The proprotein convertases furin and PACE4 play a significant role in tumor progression . Mol. Carcinog. . 28 . 2 . 63–9 . 2000 . 10900462 . 10.1002/1098-2744(200006)28:2<63::AID-MC1>3.0.CO;2-C . 22849623 .
• Moulard M, Decroly E . Maturation of HIV envelope glycoprotein precursors by cellular endoproteases . Biochim. Biophys. Acta . 1469 . 3 . 121–32 . 2001 . 11063880 . 10.1016/S0304-4157(00)00014-9 .
• Seidah NG, Prat A . Precursor convertases in the secretory pathway, cytosol and extracellular milieu . Essays Biochem. . 38 . 79–94 . 2003 . 12463163 . 10.1042/bse0380079. 528206 .
• Tsuji A, Higashine K, Hine C, Mori K, Tamai Y, Nagamune H, Matsuda Y . Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms. . Biochem. Biophys. Res. Commun. . 204 . 3 . 1381–2 . 1994 . 7980617 . 10.1006/bbrc.1994.2616 . free .
• Tsuji A, Higashine K, Hine C, Mori K, Tamai Y, Nagamune H, Matsuda Y . Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms . Biochem. Biophys. Res. Commun. . 200 . 2 . 943–50 . 1994 . 8179631 . 10.1006/bbrc.1994.1541 .
• Vollenweider F, Benjannet S, Decroly E, Savaria D, Lazure C, Thomas G, Chrétien M, Seidah NG . 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 . 1996 . 8670066 . 1217081 . 10.1042/bj3140521.
• Zhong M, Benjannet S, Lazure C, Munzer S, Seidah NG . Functional analysis of human PACE4-A and PACE4-C isoforms: identification of a new PACE4-CS isoform . FEBS Lett. . 396 . 1 . 31–6 . 1997 . 8906861 . 10.1016/0014-5793(96)01059-9 . 19890431 . free .
• Decroly E, Wouters S, Di Bello C, Lazure C, Ruysschaert JM, Seidah NG . 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 . 1997 . 8940009 . 10.1074/jbc.271.48.30442 . free .
• Inocencio NM, Sucic JF, Moehring JM, Spence MJ, Moehring TJ . 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 . 1997 . 8995442 . 10.1074/jbc.272.2.1344 . free .
• Mori K, Kii S, Tsuji A, Nagahama M, Imamaki A, Hayashi K, Akamatsu T, Nagamune H, Matsuda Y . 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 . 1997 . 9192737 . 10.1093/oxfordjournals.jbchem.a021677 .
• Tsuji A, Hine C, Tamai Y, Yonemoto K, Mori K, Yoshida S, Bando M, Sakai E, Mori K, Akamatsu T, Matsuda Y . Genomic organization and alternative splicing of human PACE4 (SPC4), kexin-like processing endoprotease . J. Biochem. . 122 . 2 . 438–52 . 1997 . 9378725 . 10.1093/oxfordjournals.jbchem.a021772 .
• Moulard M, Chaloin L, Canarelli S, Mabrouk K, Darbon H, Challoin L . Retroviral envelope glycoprotein processing: structural investigation of the cleavage site . Biochemistry . 37 . 13 . 4510–7 . 1998 . 9521771 . 10.1021/bi972662f .
• Nagahama M, Taniguchi T, Hashimoto E, Imamaki A, Mori K, Tsuji A, Matsuda Y . Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4) . FEBS Lett. . 434 . 1–2 . 155–9 . 1998 . 9738469 . 10.1016/S0014-5793(98)00970-3 . 25126519 . free .
• Viale A, Ortola C, Hervieu G, Furuta M, Barbero P, Steiner DF, Seidah NG, Nahon JL . Cellular localization and role of prohormone convertases in the processing of pro-melanin concentrating hormone in mammals . J. Biol. Chem. . 274 . 10 . 6536–45 . 1999 . 10037747 . 10.1074/jbc.274.10.6536 . free .
• Mori K, Imamaki A, Nagata K, Yonetomi Y, Kiyokage-Yoshimoto R, Martin TJ, Gillespie MT, Nagahama M, Tsuji A, Matsuda Y . Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells . J. Biochem. . 125 . 3 . 627–33 . 1999 . 10050053 . 10.1093/oxfordjournals.jbchem.a022329 .
• Sucic JF, Moehring JM, Inocencio NM, Luchini JW, Moehring TJ . 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 . 1999 . 10215603 . 1220200 . 10.1042/0264-6021:3390639 .
• Tsuji A, Yoshida S, Hasegawa S, Bando M, Yoshida I, Koide S, Mori K, Matsuda Y . 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 . 2000 . 10467164 . 10.1093/oxfordjournals.jbchem.a022478 .

Notes and References

1. KIEFER. MICHAEL C.. TUCKER. JEFFREY E.. JOH. RICHARD. LANDSBERG. KATHERINE E.. SALTMAN. DAVID. BARR. PHILIP J.. December 1991. Identification of a Second Human Subtilisin-Like Protease Gene in the fes/fps Region of Chromosome 15. DNA and Cell Biology. 10. 10. 757–769. 10.1089/dna.1991.10.757. 1741956. 1044-5498.
2. Web site: Entrez Gene: PCSK6 proprotein convertase subtilisin/kexin type 6.
3. Constam. Daniel B.. August 2014. Regulation of TGFβ and related signals by precursor processing. Seminars in Cell & Developmental Biology. 32. 85–97. 10.1016/j.semcdb.2014.01.008. 24508081. 1084-9521. free.
4. Mori. K.. Imamaki. A.. Nagata. K.. Yonetomi. Y.. Kiyokage-Yoshimoto. R.. Martin. T. J.. Gillespie. M. T.. Nagahama. M.. Tsuji. A.. Matsuda. Y.. 1999-03-01. Subtilisin-Like Proprotein Convertases, PACE4 and PC8, as Well as Furin, are Endogenous Proalbumin Convertases in HepG2 Cells. Journal of Biochemistry. 125. 3. 627–633. 10.1093/oxfordjournals.jbchem.a022329. 10050053. 0021-924X.
5. Rehemtulla. Alnawaz. Barr. Philip J.. Rhodes. Christopher J.. Kaufman. Randal J.. 1993-01-26. PACE4 is a member of the mammalian propeptidase family that has overlapping but not identical substrate specificity to PACE. Biochemistry. 32. 43. 11586–11590. 10.1021/bi00094a015. 8218226. 0006-2960.
6. Chen. Shenghan. Cao. Pengxiu. Dong. Ningzheng. Peng. Jianhao. Zhang. Chunyi. Wang. Hao. Zhou. Tiantian. Yang. Junhua. Zhang. Yue. Martelli. Elizabeth E. Naga Prasad. Sathyamangla V. 2015-08-10. PCSK6-mediated corin activation is essential for normal blood pressure. Nature Medicine. 21. 9. 1048–1053. 10.1038/nm.3920. 26259032. 4710517. 1078-8956.
7. Constam. D. B.. Robertson. E. J.. 2000-05-01. SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Genes & Development. 14. 9. 1146–1155. 10.1101/gad.14.9.1146 . 0890-9369. 316583. 10809672.
8. Berretz. Gesa. Arning. Larissa. Gerding. Wanda M.. Friedrich. Patrick. Fraenz. Christoph. Schlüter. Caroline. Epplen. Jörg T.. Güntürkün. Onur. Beste. Christian. Genç. Erhan. Ocklenburg. Sebastian. 2019-05-21. Structural Asymmetry in the Frontal and Temporal Lobes Is Associated with PCSK6 VNTR Polymorphism. Molecular Neurobiology. 56. 11. 7765–7773. 10.1007/s12035-019-01646-1. 31115778. 160009569. 0893-7648.
9. Robinson. Kelsey J.. Hurd. Peter L.. Read. Silven. Crespi. Bernard J.. April 2016. The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population. Neuropsychologia. 84. 205–212. 10.1016/j.neuropsychologia.2016.02.020. 26921480. 6142024. 0028-3932.
10. Arning. Larissa. Ocklenburg. Sebastian. Schulz. Stefanie. Ness. Vanessa. Gerding. Wanda M.. Hengstler. Jan G.. Falkenstein. Michael. Epplen. Jörg T.. Güntürkün. Onur. Beste. Christian. 2013-06-27. PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness. PLOS ONE. 8. 6. e67251. 10.1371/journal.pone.0067251. 23826248. 3695088. 2013PLoSO...867251A. 1932-6203. free.
11. Scerri. Thomas S.. Brandler. William M.. Paracchini. Silvia. Morris. Andrew P.. Ring. Susan M.. Richardson. Alex J.. Talcott. Joel B.. Stein. John. Monaco. Anthony P.. 2010-11-04. PCSK6 is associated with handedness in individuals with dyslexia. Human Molecular Genetics. 20. 3. 608–614. 10.1093/hmg/ddq475. 21051773. 3016905. 1460-2083. free.
12. Bassi. Daniel E.. Mahloogi. Haleh. Klein-Szanto. Andrés J. P.. 2000. The Proprotein Convertases Furin and PACE4 Play a Significant Role in Tumor Progression. Molecular Carcinogenesis. 28. 2. 63–69. 10.1002/1098-2744(200006)28:2<63::aid-mc1>3.0.co;2-c. 10900462. 22849623 . 0899-1987.
13. Rykaczewska. Urszula. Suur. Bianca E.. Röhl. Samuel. Razuvaev. Anton. Lengquist. Mariette. Sabater-Lleal. Maria. van der Laan. Sander W.. Miller. Clint L.. Wirka. Robert C.. Kronqvist. Malin. Gonzalez Diez. Maria. 2020-02-28. PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling. Circulation Research. 126. 5. 571–585. 10.1161/circresaha.119.316063. 31893970. 209539709. 0009-7330. free. 1887/3185300. free.
14. Constam. Daniel B.. Robertson. Elizabeth J.. 1999-01-11. Regulation of Bone Morphogenetic Protein Activity by Pro Domains and Proprotein Convertases. Journal of Cell Biology. 144. 1. 139–149. 10.1083/jcb.144.1.139. 9885250. 2148113. 0021-9525. free.
15. Constam. D B. Calfon. M. Robertson. E J. 1996-07-01. SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis.. The Journal of Cell Biology. 134. 1. 181–191. 10.1083/jcb.134.1.181. 8698813. 2120924. 0021-9525. free.
16. Mesnard. D.. 2006-05-25. Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning. Development. 133. 13. 2497–505. 10.1242/dev.02413. 16728477. 0950-1991. free.
17. Arnold. Sebastian J.. Robertson. Elizabeth J.. 2009-01-08. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nature Reviews Molecular Cell Biology. 10. 2. 91–103. 10.1038/nrm2618. 19129791. 94174. 1471-0072.
18. Brennan. J.. 2002-09-15. Nodal activity in the node governs left-right asymmetry. Genes & Development. 16. 18. 2339–2344. 10.1101/gad.1016202. 12231623. 187443. 0890-9369. free.