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.

Article Bibliography

Pubmed IDLast YearTitleAuthors
222047262011Proprotein convertases in health and disease.Artenstein AW et al
86200011996Increased proteolytic processing of protein tyrosine phosphatase mu in confluent vascular endothelial cells: the role of PC5, a member of the subtilisin family.Campan M et al
89400091996Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines.Decroly E et al
200316222009Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels.Iatan I et al
191496902009The potential anti-tumorigenic and anti-metastatic side of the proprotein convertases inhibitors.Lahlil R et al
106572492000Endoproteolytic processing of integrin pro-alpha subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7.Lissitzky JC et al
230976232012Opposite roles of furin and PC5A in N-cadherin processing.Maret D et al
89018321996Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex.Mercure C et al
227404952012Cleavage of endometrial α-integrins into their functional forms is mediated by proprotein convertase 5/6.Paule S et al
226796422012The biology and therapeutic targeting of the proprotein convertases.Seidah NG et al
237750892013The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions.Seidah NG et al
213884122011What lies ahead for the proprotein convertases?Seidah NG et al
185196392008VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.Szumska D et al
108886762000Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases.Yana I et al

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
350451022022Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease.9
350451022022Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease.9
291269842018Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone.7
291269842018Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone.7
284688282017Thrombin activation of protein C requires prior processing by a liver proprotein convertase.6
284688282017Thrombin activation of protein C requires prior processing by a liver proprotein convertase.6
253509182015Proprotein convertase 5/6a is associated with bone morphogenetic protein-2-induced squamous cell differentiation.6
254297852015Proprotein convertase 5/6 cleaves platelet-derived growth factor A in the human endometrium in preparation for embryo implantation.7
260559992015PCSK5 mutation in a patient with the VACTERL association.7
260779032015Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women.10
253509182015Proprotein convertase 5/6a is associated with bone morphogenetic protein-2-induced squamous cell differentiation.6
254297852015Proprotein convertase 5/6 cleaves platelet-derived growth factor A in the human endometrium in preparation for embryo implantation.7
260559992015PCSK5 mutation in a patient with the VACTERL association.7
260779032015Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women.10
236868572013Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport.10

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-(proprotein-convertase-subtilisin-kexin-type-5)