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PCSK5 (Proprotein Convertase Subtilisin/Kexin Type 5)

Written2014-06Majid Khatib, Beatrice Demoures
University Bordeaux 1, INSERM U1029, Avenue des Facultes, Batiment B2, Talence 33405, France

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)PC5
PC6
SPC6
Other aliasPC6A
HGNC (Hugo) PCSK5
LocusID (NCBI) 5125
Atlas_Id 52105
Location 9q21.13  [Link to chromosome band 9q21]
Location_base_pair Starts at 78505560 and ends at 78977255 bp from pter ( according to hg19-Feb_2009)  [Mapping PCSK5.png]
Fusion genes
(updated 2016)
AZGP1 (7q22.1) / PCSK5 (9q21.13)CKS2 (9q22.2) / PCSK5 (9q21.13)PCSK5 (9q21.13) / LRBA (4q31.3)
PCSK5 (9q21.13) / OSTF1 (9q21.13)

DNA/RNA

 
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.

Protein

 
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

Note
  
Entity Gastric cancer
Note Studies have shown that mice developing adenocarcinomas along the small intestine exhibited more tumours when they lack PCSK5 in enterocytes.
  
  
Entity Currarino syndrome
Note Exon sequencing of healthy individuals and patients with VACTERL malformations linked mutations in the human PCSK5 gene to this syndrome.
  
  
Entity 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

Proprotein convertases in health and disease.
Artenstein AW, Opal SM.
N Engl J Med. 2011 Dec 29;365(26):2507-18. doi: 10.1056/NEJMra1106700. (REVIEW)
PMID 22204726
 
Increased proteolytic processing of protein tyrosine phosphatase mu in confluent vascular endothelial cells: the role of PC5, a member of the subtilisin family.
Campan M, Yoshizumi M, Seidah NG, Lee ME, Bianchi C, Haber E.
Biochemistry. 1996 Mar 26;35(12):3797-802.
PMID 8620001
 
Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines.
Decroly E, Wouters S, Di Bello C, Lazure C, Ruysschaert JM, Seidah NG.
J Biol Chem. 1996 Nov 29;271(48):30442-50.
PMID 8940009
 
Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels.
Iatan I, Dastani Z, Do R, Weissglas-Volkov D, Ruel I, Lee JC, Huertas-Vazquez A, Taskinen MR, Prat A, Seidah NG, Pajukanta P, Engert JC, Genest J.
Circ Cardiovasc Genet. 2009 Oct;2(5):467-75. doi: 10.1161/CIRCGENETICS.109.877811. Epub 2009 Aug 22.
PMID 20031622
 
The potential anti-tumorigenic and anti-metastatic side of the proprotein convertases inhibitors.
Lahlil R, Calvo F, Khatib AM.
Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):83-91. (REVIEW)
PMID 19149690
 
Endoproteolytic 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, Luis J, Munzer JS, Benjannet S, Parat F, Chretien M, Marvaldi J, Seidah NG.
Biochem J. 2000 Feb 15;346 Pt 1:133-8.
PMID 10657249
 
Opposite roles of furin and PC5A in N-cadherin processing.
Maret D, Sadr MS, Sadr ES, Colman DR, Del Maestro RF, Seidah NG.
Neoplasia. 2012 Oct;14(10):880-92.
PMID 23097623
 
Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex.
Mercure C, Jutras I, Day R, Seidah NG, Reudelhuber TL.
Hypertension. 1996 Nov;28(5):840-6.
PMID 8901832
 
Cleavage of endometrial α-integrins into their functional forms is mediated by proprotein convertase 5/6.
Paule S, Aljofan M, Simon C, Rombauts LJ, Nie G.
Hum Reprod. 2012 Sep;27(9):2766-74. doi: 10.1093/humrep/des203. Epub 2012 Jun 26.
PMID 22740495
 
The biology and therapeutic targeting of the proprotein convertases.
Seidah NG, Prat A.
Nat Rev Drug Discov. 2012 May;11(5):367-83. (REVIEW)
PMID 22679642
 
The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions.
Seidah NG, Sadr MS, Chretien M, Mbikay M.
J Biol Chem. 2013 Jul 26;288(30):21473-81. doi: 10.1074/jbc.R113.481549. Epub 2013 Jun 17. (REVIEW)
PMID 23775089
 
What lies ahead for the proprotein convertases?
Seidah NG.
Ann N Y Acad Sci. 2011 Mar;1220:149-61. doi: 10.1111/j.1749-6632.2010.05883.x. (REVIEW)
PMID 21388412
 
VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.
Szumska D, Pieles G, Essalmani R, Bilski M, Mesnard D, Kaur K, Franklyn A, El Omari K, Jefferis J, Bentham J, Taylor JM, Schneider JE, Arnold SJ, Johnson P, Tymowska-Lalanne Z, Stammers D, Clarke K, Neubauer S, Morris A, Brown SD, Shaw-Smith C, Cama A, Capra V, Ragoussis J, Constam D, Seidah NG, Prat A, Bhattacharya S.
Genes Dev. 2008 Jun 1;22(11):1465-77. doi: 10.1101/gad.479408.
PMID 18519639
 
Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases.
Yana I, Weiss SJ.
Mol Biol Cell. 2000 Jul;11(7):2387-401.
PMID 10888676
 

Citation

This paper should be referenced as such :
M Khatib, B Demoures
PCSK5 (Proprotein Convertase Subtilisin/Kexin Type 5)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):191-193.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PCSK5ID52105ch9q21.html


External links

Nomenclature
HGNC (Hugo)PCSK5   8747
Cards
AtlasPCSK5ID52105ch9q21
Entrez_Gene (NCBI)PCSK5  5125  proprotein convertase subtilisin/kexin type 5
AliasesPC5; PC6; PC6A; SPC6
GeneCards (Weizmann)PCSK5
Ensembl hg19 (Hinxton)ENSG00000099139 [Gene_View]  chr9:78505560-78977255 [Contig_View]  PCSK5 [Vega]
Ensembl hg38 (Hinxton)ENSG00000099139 [Gene_View]  chr9:78505560-78977255 [Contig_View]  PCSK5 [Vega]
ICGC DataPortalENSG00000099139
TCGA cBioPortalPCSK5
AceView (NCBI)PCSK5
Genatlas (Paris)PCSK5
WikiGenes5125
SOURCE (Princeton)PCSK5
Genetics Home Reference (NIH)PCSK5
Genomic and cartography
GoldenPath hg19 (UCSC)PCSK5  -     chr9:78505560-78977255 +  9q21.13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PCSK5  -     9q21.13   [Description]    (hg38-Dec_2013)
EnsemblPCSK5 - 9q21.13 [CytoView hg19]  PCSK5 - 9q21.13 [CytoView hg38]
Mapping of homologs : NCBIPCSK5 [Mapview hg19]  PCSK5 [Mapview hg38]
OMIM600488   
Gene and transcription
Genbank (Entrez)AI379031 AK023096 AK056202 AK122718 AK225773
RefSeq transcript (Entrez)NM_001190482 NM_006200
RefSeq genomic (Entrez)NC_000009 NC_018920 NG_029445 NT_008470 NW_004929366
Consensus coding sequences : CCDS (NCBI)PCSK5
Cluster EST : UnigeneHs.732073 [ NCBI ]
CGAP (NCI)Hs.732073
Alternative Splicing GalleryENSG00000099139
Gene ExpressionPCSK5 [ NCBI-GEO ]   PCSK5 [ EBI - ARRAY_EXPRESS ]   PCSK5 [ SEEK ]   PCSK5 [ MEM ]
Gene Expression Viewer (FireBrowse)PCSK5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5125
GTEX Portal (Tissue expression)PCSK5
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92824   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92824  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92824
Splice isoforms : SwissVarQ92824
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
PhosPhoSitePlusQ92824
Domaine pattern : Prosite (Expaxy)SUBTILASE_ASP (PS00136)    SUBTILASE_HIS (PS00137)    SUBTILASE_SER (PS00138)   
Domains : Interpro (EBI)EGF-like_dom    Furin_repeat    Galactose-bd-like    GF_recep_IV    Growth_fac_rcpt_    Peptidase_S8/S53_dom    Peptidase_S8_Asp-AS    Peptidase_S8_His-AS    Peptidase_S8_Ser-AS    Peptidase_S8_subtilisin-rel    Prot_inh_propept    PrprotnconvertsP    S8_pro-domain   
Domain families : Pfam (Sanger)GF_recep_IV (PF14843)    P_proprotein (PF01483)    Peptidase_S8 (PF00082)    S8_pro-domain (PF16470)   
Domain families : Pfam (NCBI)pfam14843    pfam01483    pfam00082    pfam16470   
Domain families : Smart (EMBL)EGF (SM00181)  FU (SM00261)  
Conserved Domain (NCBI)PCSK5
DMDM Disease mutations5125
Blocks (Seattle)PCSK5
SuperfamilyQ92824
Human Protein AtlasENSG00000099139
Peptide AtlasQ92824
HPRD08985
IPIIPI00294862   IPI01010025   IPI00746753   IPI00479956   IPI00873797   
Protein Interaction databases
DIP (DOE-UCLA)Q92824
IntAct (EBI)Q92824
FunCoupENSG00000099139
BioGRIDPCSK5
STRING (EMBL)PCSK5
ZODIACPCSK5
Ontologies - Pathways
QuickGOQ92824
Ontology : AmiGOkidney development  kidney development  renin secretion into blood stream  cardiac septum development  serine-type endopeptidase activity  protein binding  extracellular space  extracellular space  Golgi apparatus  Golgi apparatus  Golgi lumen  signal peptide processing  cell-cell signaling  determination of left/right symmetry  heart development  embryo implantation  peptidase activity  anterior/posterior pattern specification  integral component of membrane  protein processing  peptide hormone processing  viral life cycle  viral life cycle  secretory granule  respiratory tube development  nerve growth factor processing  limb morphogenesis  cytokine biosynthetic process  peptide binding  peptide biosynthetic process  embryonic digestive tract development  embryonic digestive tract development  embryonic skeletal system development  embryonic skeletal system development  coronary vasculature development  
Ontology : EGO-EBIkidney development  kidney development  renin secretion into blood stream  cardiac septum development  serine-type endopeptidase activity  protein binding  extracellular space  extracellular space  Golgi apparatus  Golgi apparatus  Golgi lumen  signal peptide processing  cell-cell signaling  determination of left/right symmetry  heart development  embryo implantation  peptidase activity  anterior/posterior pattern specification  integral component of membrane  protein processing  peptide hormone processing  viral life cycle  viral life cycle  secretory granule  respiratory tube development  nerve growth factor processing  limb morphogenesis  cytokine biosynthetic process  peptide binding  peptide biosynthetic process  embryonic digestive tract development  embryonic digestive tract development  embryonic skeletal system development  embryonic skeletal system development  coronary vasculature development  
REACTOMEQ92824 [protein]
REACTOME Pathways167060 [pathway]   174800 [pathway]   
NDEx NetworkPCSK5
Atlas of Cancer Signalling NetworkPCSK5
Wikipedia pathwaysPCSK5
Orthology - Evolution
OrthoDB5125
GeneTree (enSembl)ENSG00000099139
Phylogenetic Trees/Animal Genes : TreeFamPCSK5
HOVERGENQ92824
HOGENOMQ92824
Homologs : HomoloGenePCSK5
Homology/Alignments : Family Browser (UCSC)PCSK5
Gene fusions - Rearrangements
Fusion : MitelmanCKS2/PCSK5 [9q22.2/9q21.13]  [t(9;9)(q21;q22)]  
Fusion : MitelmanPCSK5/LRBA [9q21.13/4q31.3]  [t(4;9)(q31;q21)]  
Fusion : MitelmanPCSK5/OSTF1 [9q21.13/9q21.13]  [t(9;9)(q21;q21)]  
Fusion: TCGACKS2 9q22.2 PCSK5 9q21.13 LGG
Fusion: TCGAPCSK5 9q21.13 OSTF1 9q21.13 LUAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPCSK5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PCSK5
dbVarPCSK5
ClinVarPCSK5
1000_GenomesPCSK5 
Exome Variant ServerPCSK5
ExAC (Exome Aggregation Consortium)PCSK5 (select the gene name)
Genetic variants : HAPMAP5125
Genomic Variants (DGV)PCSK5 [DGVbeta]
DECIPHER (Syndromes)9:78505560-78977255  ENSG00000099139
CONAN: Copy Number AnalysisPCSK5 
Mutations
ICGC Data PortalPCSK5 
TCGA Data PortalPCSK5 
Broad Tumor PortalPCSK5
OASIS PortalPCSK5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPCSK5  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPCSK5
intOGen PortalPCSK5
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PCSK5
DgiDB (Drug Gene Interaction Database)PCSK5
DoCM (Curated mutations)PCSK5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PCSK5 (select a term)
intoGenPCSK5
NCG5 (London)PCSK5
Cancer3DPCSK5(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600488   
Orphanet
MedgenPCSK5
Genetic Testing Registry PCSK5
NextProtQ92824 [Medical]
TSGene5125
GENETestsPCSK5
Huge Navigator PCSK5 [HugePedia]
snp3D : Map Gene to Disease5125
BioCentury BCIQPCSK5
ClinGenPCSK5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5125
Chemical/Pharm GKB GenePA33093
Clinical trialPCSK5
Miscellaneous
canSAR (ICR)PCSK5 (select the gene name)
Probes
Litterature
PubMed80 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePCSK5
EVEXPCSK5
GoPubMedPCSK5
iHOPPCSK5
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Mar 30 13:13:55 CEST 2017

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