Biology:PCSK6

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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,[5][4][3] and cardiovascular diseases.[6][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,[3] pro-albumin,[4] von Willebrand factor,[5] and corin.[6] Alternatively spliced transcript variants encoding different isoforms have been identified.[2]

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.[3][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.[7]

In humans, Pcsk6 VNTR polymorphism is associated with the structural asymmetry of the frontal and temporal lobe,[8] and  degree of handedness.[9][10]

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.[6] A hypertensive patient was found to have a G/A mutation on the PCSK6 gene that resulted in a Asp282Asn (D282N) substitution at the Pcsk6 catalytic domain, which in turn, hinders corin processing.[6] In vascular remodeling, Pcsk6 was found to induce smooth muscle cell migration in response to PDGFB by activating MMP14.[13] When Pcsk6 was knocked out, the intimal hyperplasia response to in vivo carotid ligation was lowered.[13]

Other: This gene is thought to play a role in tumor progression.[2][12]

References

  1. ↑ 1.0 1.1 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. doi:10.1089/dna.1991.10.757. ISSN 1044-5498. PMID 1741956. 
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: PCSK6 proprotein convertase subtilisin/kexin type 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5046. 
  3. ↑ 3.0 3.1 3.2 3.3 Constam, Daniel B. (August 2014). "Regulation of TGFβ and related signals by precursor processing". Seminars in Cell & Developmental Biology 32: 85–97. doi:10.1016/j.semcdb.2014.01.008. ISSN 1084-9521. PMID 24508081. 
  4. ↑ 4.0 4.1 4.2 Mori, K.; Imamaki, A.; Nagata, K.; Yonetomi, Y.; Kiyokage-Yoshimoto, R.; Martin, T. J.; Gillespie, M. T.; Nagahama, M. et al. (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. ISSN 0021-924X. PMID 10050053. 
  5. ↑ 5.0 5.1 5.2 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. doi:10.1021/bi00094a015. ISSN 0006-2960. PMID 8218226. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Chen, Shenghan; Cao, Pengxiu; Dong, Ningzheng; Peng, Jianhao; Zhang, Chunyi; Wang, Hao; Zhou, Tiantian; Yang, Junhua et al. (2015-08-10). "PCSK6-mediated corin activation is essential for normal blood pressure". Nature Medicine 21 (9): 1048–1053. doi:10.1038/nm.3920. ISSN 1078-8956. PMID 26259032. 
  7. ↑ 7.0 7.1 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. doi:10.1101/gad.14.9.1146. ISSN 0890-9369. PMID 10809672. 
  8. ↑ 8.0 8.1 Berretz, Gesa; Arning, Larissa; Gerding, Wanda M.; Friedrich, Patrick; Fraenz, Christoph; Schlüter, Caroline; Epplen, Jörg T.; Güntürkün, Onur et al. (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. ISSN 0893-7648. PMID 31115778. 
  9. ↑ 9.0 9.1 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. doi:10.1016/j.neuropsychologia.2016.02.020. ISSN 0028-3932. PMID 26921480. 
  10. ↑ 10.0 10.1 Arning, Larissa; Ocklenburg, Sebastian; Schulz, Stefanie; Ness, Vanessa; Gerding, Wanda M.; Hengstler, Jan G.; Falkenstein, Michael; Epplen, Jörg T. et al. (2013-06-27). "PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness". PLOS ONE 8 (6): e67251. doi:10.1371/journal.pone.0067251. ISSN 1932-6203. PMID 23826248. Bibcode: 2013PLoSO...867251A. 
  11. ↑ Scerri, Thomas S.; Brandler, William M.; Paracchini, Silvia; Morris, Andrew P.; Ring, Susan M.; Richardson, Alex J.; Talcott, Joel B.; Stein, John et al. (2010-11-04). "PCSK6 is associated with handedness in individuals with dyslexia". Human Molecular Genetics 20 (3): 608–614. doi:10.1093/hmg/ddq475. ISSN 1460-2083. PMID 21051773. 
  12. ↑ 12.0 12.1 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. doi:10.1002/1098-2744(200006)28:2<63::aid-mc1>3.0.co;2-c. ISSN 0899-1987. PMID 10900462. 
  13. ↑ 13.0 13.1 13.2 Rykaczewska, Urszula; Suur, Bianca E.; Röhl, Samuel; Razuvaev, Anton; Lengquist, Mariette; Sabater-Lleal, Maria; van der Laan, Sander W.; Miller, Clint L. et al. (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. doi:10.1161/circresaha.119.316063. ISSN 0009-7330. PMID 31893970. https://discovery.ucl.ac.uk/id/eprint/10095741/. 
  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. doi:10.1083/jcb.144.1.139. ISSN 0021-9525. PMID 9885250. 
  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. doi:10.1083/jcb.134.1.181. ISSN 0021-9525. PMID 8698813. 
  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. doi:10.1242/dev.02413. ISSN 0950-1991. PMID 16728477. 
  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. doi:10.1038/nrm2618. ISSN 1471-0072. PMID 19129791. 
  18. ↑ Brennan, J. (2002-09-15). "Nodal activity in the node governs left-right asymmetry". Genes & Development 16 (18): 2339–2344. doi:10.1101/gad.1016202. ISSN 0890-9369. PMID 12231623. 

Further reading




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