Proprotein convertase subtilisin/kexin type 6 is an
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
that in humans is encoded by the ''PCSK6''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
which is located in chromosome 15.
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,
pro-albumin,
von Willebrand factor,
and corin.
Clinically, Pcsk6 is suggested to play a role in left/right asymmetry,
structural asymmetry of the brain,
handedness,
tumor progression,
hemostasis,
and cardiovascular diseases.
Function
The protein encoded by this gene belongs to the
subtilisin
Subtilisin is a protease (a protein-digesting enzyme) initially obtained from ''Bacillus subtilis''.
Subtilisins belong to subtilases, a group of serine proteases that – like all serine proteases – initiate the nucleophilic attack on the p ...
-like
proprotein convertase Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove thos ...
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
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
-dependent serine
endoprotease
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this re ...
that can cleave precursor protein at their paired basic amino acid processing sites. Some of its substrates are -
transforming growth factor beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
related proteins,
pro-albumin,
von Willebrand factor
Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopen ...
,
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.
Elevated levels of Pcsk6 was detected in maternal decidual cells of the implantation site and the extraembryonic
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...
.
The regulation of proper gradient of Nodal and BMPs is crucial for gastrulation, proximal-distal axis, and establishment of left-right axis patterning.
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 a 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.
References
Further reading
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