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PCSK4 (proprotein convertase subtilisin/kexin type 4)

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)


Alias (NCBI)PC4
HGNC Alias symbPC4
LocusID (NCBI) 54760
Atlas_Id 50716
Location 19p13.3  [Link to chromosome band 19p13]
Location_base_pair Starts at 1481428 and ends at 1490450 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PCSK4.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PCSK4 (19p13.3) / P2RX3 (11q12.1)


Description This gene can be found on chromosome 19 at location: at 1432427 and ends at 1441410.
Transcription The DNA sequence contains 15 exons and the transcript length: 2661 bps translated to a 755 residues protein.


Description PCSK4 is a member of the family of subtilisin-like proprotein convertase (PCs) that process protein at basic residues. This protein is produced in the inactive zymogen form and is activated by proteolytic removal of its prodomain in the N-terminal site.
Expression PCSK4 is restricted to the reproductive tract and expressed primarily in testicular germ cells and sperm. Low levels of PCSK4 mRNA have also been detected in ovaries and the placenta.
Localisation PCSK4 exact intracellular location has not yet been determined.
Function PCSK4 cleaves synthetic peptide substrates after an Arg in a basic sequence context; most often after paired basic residues (K/R-X-K/R), to release mature proteins from their proproteins. PCSK4 substrates include growth factors (DEAF-1, proIGF2, proenkephalin, proNGF, proPACAP, HGFR), receptors (IGF-1R, HGFR), and members of the ADAM (a-disintegrin-and-metalloproteinase) family (ADAM-1, ADAM-2, ADAM-3, ADAM-5. The activation/inactivation of these substrates implicated directly the latter to the regulation of gonadal functions, sperm motility, and species specific reproduction.
Homology The PCSK4 catalytic domain has a high percentage of homology with those of the other PCs: 70% between PCSK4 and Furin.

Implicated in

Entity Pregnancy difficulties
Note An aberrant processing of IGF-II by PCSK4 plays a role in inadequate trophoblast migration and, thus, fetal growth restriction.
Entity Infertility
Note The fertilizing ability of PCSK4 null spermatozoa was also found to be significantly reduced. Moreover, PCSK4 cleavages lead to sperm acquisition of fertilization competence.


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
Enzymic characterization in vitro of recombinant proprotein convertase PC4.
Basak A, Toure BB, Lazure C, Mbikay M, Chretien M, Seidah NG.
Biochem J. 1999 Oct 1;343 Pt 1:29-37.
PMID 10493908
In vitro elucidation of substrate specificity and bioassay of proprotein convertase 4 using intramolecularly quenched fluorogenic peptides.
Basak S, Chretien M, Mbikay M, Basak A.
Biochem J. 2004 Jun 1;380(Pt 2):505-14.
PMID 14972029
Proprotein convertases: "master switches" in the regulation of tumor growth and progression.
Bassi DE, Fu J, Lopez de Cicco R, Klein-Szanto AJ.
Mol Carcinog. 2005 Nov;44(3):151-61. (REVIEW)
PMID 16167351
Peptide-protein interactions suggest that acetylation of lysines 381 and 382 of p53 is important for positive coactivator 4-p53 interaction.
Debnath S, Chatterjee S, Arif M, Kundu TK, Roy S.
J Biol Chem. 2011 Jul 15;286(28):25076-87. doi: 10.1074/jbc.M110.205328. Epub 2011 May 17.
PMID 21586571
Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review.
Gyamera-Acheampong C, Mbikay M.
Hum Reprod Update. 2009 Mar-Apr;15(2):237-47. doi: 10.1093/humupd/dmn060. Epub 2008 Dec 24. (REVIEW)
PMID 19109312
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
Role of pro-IGF-II processing by proprotein convertase 4 in human placental development.
Qiu Q, Basak A, Mbikay M, Tsang BK, Gruslin A.
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11047-52. Epub 2005 Jul 22.
PMID 16040806
Proprotein convertases: lessons from knockouts.
Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM.
FASEB J. 2006 Oct;20(12):1954-63. (REVIEW)
PMID 17012247
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
Alteration in the processing of the ACRBP/sp32 protein and sperm head/acrosome malformations in proprotein convertase 4 (PCSK4) null mice.
Tardif S, Guyonnet B, Cormier N, Cornwall GA.
Mol Hum Reprod. 2012 Jun;18(6):298-307. doi: 10.1093/molehr/gas009. Epub 2012 Feb 21.
PMID 22357636
Genetics of the first seven proprotein convertase enzymes in health and disease.
Turpeinen H, Ortutay Z, Pesu M.
Curr Genomics. 2013 Nov;14(7):453-67. doi: 10.2174/1389202911314050010.
PMID 24396277


This paper should be referenced as such :
M Khatib, B Demoures
PCSK4 (proprotein convertase subtilisin/kexin type 4)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):189-190.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)PCSK4   8746
Entrez_Gene (NCBI)PCSK4    proprotein convertase subtilisin/kexin type 4
AliasesPC4; SPC5
GeneCards (Weizmann)PCSK4
Ensembl hg19 (Hinxton)ENSG00000115257 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000115257 [Gene_View]  ENSG00000115257 [Sequence]  chr19:1481428-1490450 [Contig_View]  PCSK4 [Vega]
ICGC DataPortalENSG00000115257
TCGA cBioPortalPCSK4
Genatlas (Paris)PCSK4
SOURCE (Princeton)PCSK4
Genetics Home Reference (NIH)PCSK4
Genomic and cartography
GoldenPath hg38 (UCSC)PCSK4  -     chr19:1481428-1490450 -  19p13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PCSK4  -     19p13.3   [Description]    (hg19-Feb_2009)
GoldenPathPCSK4 - 19p13.3 [CytoView hg19]  PCSK4 - 19p13.3 [CytoView hg38]
genome Data Viewer NCBIPCSK4 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA453604 AK057235 AK302079 AL043305 AL133566
RefSeq transcript (Entrez)NM_017573
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PCSK4
Alternative Splicing GalleryENSG00000115257
Gene ExpressionPCSK4 [ NCBI-GEO ]   PCSK4 [ EBI - ARRAY_EXPRESS ]   PCSK4 [ SEEK ]   PCSK4 [ MEM ]
Gene Expression Viewer (FireBrowse)PCSK4 [ Firebrowse - Broad ]
GenevisibleExpression of PCSK4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54760
GTEX Portal (Tissue expression)PCSK4
Human Protein AtlasENSG00000115257-PCSK4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6UW60   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6UW60  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6UW60
Splice isoforms : SwissVarQ6UW60
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   [ MEROPS ]
Domaine pattern : Prosite (Expaxy)P_HOMO_B (PS51829)    SUBTILASE (PS51892)    SUBTILASE_ASP (PS00136)    SUBTILASE_HIS (PS00137)    SUBTILASE_SER (PS00138)   
Domains : Interpro (EBI)Furin_repeat    Galactose-bd-like_sf    Growth_fac_rcpt_cys_sf    Kexin/furin    P_dom    Peptidase_S8/S53_dom    Peptidase_S8/S53_dom_sf    Peptidase_S8_Asp-AS    Peptidase_S8_His-AS    Peptidase_S8_Ser-AS    Peptidase_S8_subtilisin-rel    S8_pro-domain    S8_pro-domain_sf   
Domain families : Pfam (Sanger)P_proprotein (PF01483)    Peptidase_S8 (PF00082)    S8_pro-domain (PF16470)   
Domain families : Pfam (NCBI)pfam01483    pfam00082    pfam16470   
Domain families : Smart (EMBL)FU (SM00261)  
Conserved Domain (NCBI)PCSK4
Blocks (Seattle)PCSK4
Human Protein Atlas [tissue]ENSG00000115257-PCSK4 [tissue]
Peptide AtlasQ6UW60
IPIIPI00419591   IPI00241523   IPI00902830   IPI00908911   
Protein Interaction databases
IntAct (EBI)Q6UW60
Ontologies - Pathways
Ontology : AmiGOacrosomal vesicle  acrosomal membrane  serine-type endopeptidase activity  protein binding  trans-Golgi network  binding of sperm to zona pellucida  acrosome reaction  fertilization  membrane  protein processing  protein processing  peptide hormone processing  reproductive process  integral component of Golgi membrane  sperm capacitation  
Ontology : EGO-EBIacrosomal vesicle  acrosomal membrane  serine-type endopeptidase activity  protein binding  trans-Golgi network  binding of sperm to zona pellucida  acrosome reaction  fertilization  membrane  protein processing  protein processing  peptide hormone processing  reproductive process  integral component of Golgi membrane  sperm capacitation  
NDEx NetworkPCSK4
Atlas of Cancer Signalling NetworkPCSK4
Wikipedia pathwaysPCSK4
Orthology - Evolution
GeneTree (enSembl)ENSG00000115257
Phylogenetic Trees/Animal Genes : TreeFamPCSK4
Homologs : HomoloGenePCSK4
Homology/Alignments : Family Browser (UCSC)PCSK4
Gene fusions - Rearrangements
Fusion : Fusion_HubPCSK4--P2RX3   
Fusion : QuiverPCSK4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPCSK4 [hg38]
Exome Variant ServerPCSK4
GNOMAD BrowserENSG00000115257
Varsome BrowserPCSK4
Genomic Variants (DGV)PCSK4 [DGVbeta]
DECIPHERPCSK4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPCSK4 
ICGC Data PortalPCSK4 
TCGA Data PortalPCSK4 
Broad Tumor PortalPCSK4
OASIS PortalPCSK4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPCSK4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPCSK4
Mutations and Diseases : HGMDPCSK4
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 PCSK4
DgiDB (Drug Gene Interaction Database)PCSK4
DoCM (Curated mutations)PCSK4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PCSK4 (select a term)
NCG6 (London) select PCSK4
Cancer3DPCSK4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry PCSK4
NextProtQ6UW60 [Medical]
Target ValidationPCSK4
Huge Navigator PCSK4 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTD
Pharm GKB GenePA33092
Clinical trialPCSK4
canSAR (ICR)PCSK4 (select the gene name)
DataMed IndexPCSK4
PubMed23 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Feb 19 17:57:07 CET 2021

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