Proprotein convertase subtilisin/kexin type 6 is an protease that in humans is encoded by the PCSK6gene which is located in chromosome 15.[5][6] 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.[5] Active Pcsk6 has been reported to process substrates such as transforming growth factor β,[7] pro-albumin,[8] von Willebrand factor,[9] and corin.[10] Clinically, Pcsk6 is suggested to play a role in left/right asymmetry,[11] structural asymmetry of the brain,[12] handedness,[13][14][15] tumor progression,[16] hemostasis,[9][8][7] and cardiovascular diseases.[10][17]
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,[7] pro-albumin,[8]von Willebrand factor,[9] and corin.[10] Alternatively spliced transcript variants encoding different isoforms have been identified.[6]
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.[7][18] Elevated levels of Pcsk6 was detected in maternal decidual cells of the implantation site and the extraembryonic ectoderm.[19] The regulation of proper gradient of Nodal and BMPs is crucial for gastrulation,[20] proximal-distal axis,[21] and establishment of left-right axis patterning.[22]
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.[11]
In humans, Pcsk6 VNTR polymorphism is associated with the structural asymmetry of the frontal and temporal lobe,[12] and degree of handedness.[13][14]
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.[10] 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.[10] In vascular remodeling, Pcsk6 was found to induce smooth muscle cell migration in response to PDGFB by activating MMP14.[17] When Pcsk6 was knocked out, the intimal hyperplasia response to in vivo carotid ligation was lowered.[17]
Other: This gene is thought to play a role in tumor progression.[6][16]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ abKIEFER, 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. doi:10.1089/dna.1991.10.757. ISSN1044-5498. PMID1741956.
^ abcMori, 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. doi:10.1093/oxfordjournals.jbchem.a022329. ISSN0021-924X. PMID10050053.
^ abcRehemtulla, 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. doi:10.1021/bi00094a015. ISSN0006-2960. PMID8218226.
^ abBerretz, 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. doi:10.1007/s12035-019-01646-1. ISSN0893-7648. PMID31115778. S2CID160009569.
^ abRobinson, 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. doi:10.1016/j.neuropsychologia.2016.02.020. ISSN0028-3932. PMID26921480. S2CID6142024.
^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. doi:10.1038/nrm2618. ISSN1471-0072. PMID19129791. S2CID94174.
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. PMID11063880.
Seidah NG, Prat A (2003). "Precursor convertases in the secretory pathway, cytosol and extracellular milieu". Essays Biochem. 38: 79–94. doi:10.1042/bse0380079. PMID12463163. S2CID528206.
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. PMID9192737.
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. PMID9378725.
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. PMID9521771.
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. PMID10050053.
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. PMID10467164.
