Proprotein convertase subtilisin/kexin type 6 is anprotease that in humans is encoded by thePCSK6gene 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]
The protein encoded by this gene belongs to thesubtilisin-likeproprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is acalcium-dependent serineendoprotease 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]
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 extraembryonicectoderm.[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 toin 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.
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^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.
^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.
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.PMID8179631.
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.
