PCSK5 (Proprotein Convertase Subtilisin/Kexin Type 5)

2014-06-01   Majid Khatib , Béatrice Demoures 

University Bordeaux 1, INSERM U1029, Avenue des Facultes, Batiment B2, Talence 33405, France

Identity

HGNC
LOCATION
9q21.13
LOCUSID
ALIAS
PC5,PC6,PC6A,SPC6
FUSION GENES

DNA/RNA

Atlas Image

Description

This gene can be found on chromosome 9 at location: 77695406-78164112.

Transcription

The DNA sequence contains 37 exons and the transcript length: 9538 bps translated to 1860 residues protein.

Proteins

Atlas Image

Description

PCSK5 is a member of the family of subtilisin-like proprotein convertase (PCs) that process proteins at basic residues. This protease undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER. It then sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired.

Expression

PCSK5 is widely expressed and encoded by two alternatively spliced mRNAs: PC5A (which encodes a soluble 913-amino acid protein) and PC5B (which encodes a type I membrane-bound 1860-amino acid enzyme). PC5A is mostly found in the adrenal gland, uterus, ovary, aorta, brain and lung. PC5B is more limited with high expression in the intestine (jejunum, duodenum, ileum, colon), the kidney and the liver.

Localisation

Isoform PC6A: Secreted.
Isoform PC6B: Endomembrane system: Type I membrane protein localized

Function

PCSK5 is capable of cleavage at the R-X-(K/R)-R consensus motif to release mature proteins from their proproteins. PCSK5 substrates include growth factors (GDF11, TGFb, BMP2, CALD1, NGF, PDGF-A, PDGF-B, VEGF-C), receptors (IGF-1R), prohormones (pro-renin), ECM proteins (N-cadherin, alpha-integrins), enzymes (phospholipase, pro-MT1-MMP, ADAM family), and viral protein (HIV-1 glycoprotein gp160). The activation/inactivation of these substrates implicated directly the latter to homeostatic balance, HDL metabolism, pregnancy establishment and development, and to cell adhesion, proliferation and migration.

Homology

The PCSK5 catalytic domain has a high percentage of homology with those of the other PCs: 65% between PCSK5 and Furin.

Implicated in

Entity name
Gastric cancer
Note
Studies have shown that mice developing adenocarcinomas along the small intestine exhibited more tumours when they lack PCSK5 in enterocytes.
Entity name
Currarino syndrome
Note
Exon sequencing of healthy individuals and patients with VACTERL malformations linked mutations in the human PCSK5 gene to this syndrome.
Entity name
Viral infection
Note
The human immunodeficiency virus HIV envelope glycoprotein gp160 is synthesized as an inactive precursor, which is processed into its fusiogenic form gp120/gp41 by host cell PCSK5 during its intracellular trafficking.

Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 5125
MIM: 600488
HGNC: 8747
Ensembl: ENSG00000099139

Variants:

dbSNP: 5125
ClinVar: 5125
TCGA: ENSG00000099139
COSMIC: PCSK5

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000099139ENST00000376752Q92824
ENSG00000099139ENST00000376767B1AMG5
ENSG00000099139ENST00000424854Q5JSG7
ENSG00000099139ENST00000455778B1AMG8
ENSG00000099139ENST00000545128Q92824

Expression (GTEx)

0
5
10
15

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF processingREACTOMER-HSA-167060
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Lipid digestion, mobilization, and transportREACTOMER-HSA-73923
Lipoprotein metabolismREACTOMER-HSA-174824
Chylomicron-mediated lipid transportREACTOMER-HSA-174800

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
169120352006The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.74
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
185196392008VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.42
172421582007Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.39
180396502008The regulated cell surface zymogen activation of the proprotein convertase PC5A directs the processing of its secretory substrates.35
117231182002Inhibitory potency and specificity of subtilase-like pro-protein convertase (SPC) prodomains.33
182458192008Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9.22
159116962005Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis.18
200316222009Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels.11

Citation

Majid Khatib ; Béatrice Demoures

PCSK5 (Proprotein Convertase Subtilisin/Kexin Type 5)

Atlas Genet Cytogenet Oncol Haematol. 2014-06-01

Online version: http://atlasgeneticsoncology.org/gene/52105/pcsk5