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PCSK1 (proprotein convertase subtilisin/kexin type 1)

Written2017-09Béatrice Demoures, Géraldine Siegfried and Abdel-Majid Khatib
INSERM U1029, Université Bordeaux,Pessac, France

Abstract PCSK1 is a serine protease involved in the proteolytic processing of a variety of protein precursors mainly neuropeptides and prohormones. In 1991, PC1/3; also known as PCSK1, PC1, PC3, and SPC3 was identified at the same time by two laboratories separately. The human and mouse PCSK1 genes are localized on chromosomes 5 and 13, respectively. The cleavage of these protein precursors is required for the mediation of their functions including the regulation of glucose homeostasis and food intake. The PCSK1 substrates that regulate these functions include proinsulin, proglucagon, proghrelin and proopiomelanocortin and others. PCSK1 polymorphisms were associated with risk of obesity and with various endocrine disorders. PCSK1 is also involved in the regulation of macrophage activation and cytokine secretion. The inhibition of PCSK1 activity was proposed to reverse the macrophage phenotype from an M2-like to an M1-like phenotype. PCSK1 is highly expressed in breast cancers and in neuroendocrine tumors including carcinoid tumors. The expression of this protease at the RNA and protein levels is also increased in liver colorectal metastasis, suggesting PCSK1 activity in tumorigenesis, however the evidence of PCSK1 roles in these cancers and probably others remain to be defined.

Keywords PCSK1, PC1, endocrine disorders, cancer, chromosome 5.

(Note : for Links provided by Atlas : click)


Alias (NCBI)NEC1
HGNC Alias symbPC1
HGNC Alias nameprohormone convertase 3
 prohormone convertase 1
 proprotein convertase 1
HGNC Previous nameNEC1
HGNC Previous nameneuroendocrine convertase 1
LocusID (NCBI) 5122
Atlas_Id 41671
Location 5q15  [Link to chromosome band 5q15]
Location_base_pair Starts at 96390336 and ends at 96432159 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PCSK1.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)


  Figure 1: Genomic organization of PCSK1.
Description The PCSK1 gene is located on chromosome 5q15-21 in humans, and chromosome 13c in the mouse (Seidah NG et al. 1991a, Seidah NG et al. 1991b). The promoter of this gene contains cAMP-response elements (CRE-1 and CRE-2). Transcription factors such as cAMP-responsive element-binding protein 1 ( CREB1) and Activating Transcription Factor 1 ( ATF1) that can transactivate the PCSK1 promoter (Jansen E et al, 1997, Espinosa VP et al, 2008).
Transcription The DNA sequence of PCSK1contains 14 exons and the transcript length of 5068 bps is translated to a 753 residues protein. 4 spliced variants of PCSK1 are identified (splice variants) that code for 3 protein isoforms of 753 aa, 706 aa and 157 aa in length, respectively (M_000439, NM_001177875).


  Figure 2: Diagram representing the protein structure of PCSK1. PCSK1 is a multi-domain serine proteinase consisting of a signal peptide followed by prosegment, catalytic, middle, and cytoplasmic domain. The P domain just after the catalytic domain is required for the stabilization of the catalytic domain. The C-terminal domain is involved in the routing of PC1/3 to the secretory granules. 
Description PCSK1 is the third member of the proprotein convertase Subtilisin/Kexin-like family that was cloned from mammalian organisms, after furin and PC2 (Seidah NG et al. 1991, Smeekens SP et al, 1991, reviewed in Scamuffa N et al, 2006). The domain structure of PCSK1 precursor consists of four domains that include a prodomain (or prosegment), a catalytic domain, a P domain, and a carboxy-terminal domain (Figure 2). The propeptide domain is essential for the appropriate protein folding and exit from the endoplasmic reticulum (ER) of PCSK1 (Creemers JW1 et al, 1995). The catalytic domain is highly conserved among various species. Similar to the other members of the subtilisin superfamily the amino acids Asp, His, and Ser form the catalytic triad. The P domain presents a key role in the regulation of the PCSK1 activity through calcium and pH modulation (Zhou A1 et al, 1998). The carboxy-terminal domain is mainly involved in PCSK1 sorting into secretory granules (Dikeakos JD et al. 2009).
After the production of PCSK1 preproform in the endoplasmic reticulum and removal of its signal peptide, the 94kDa precursor of PCSK1 activation occurs after both N-and C-terminal domains cleavages. The 94kDa precursor undergoes an initial autocatalytic processing of its prosegment (prodomain). After protein scaffold and N-glycosylation, proPCSK1 exits the ER and sorts to the trans-Golgi network. In the early compartment, proPCSK1 is sulfated on its sugar residues. Lately during progression to the mildly acidic environment, an autocatalytic cleavage occurs to remove the prodomain and generates a 87kDa active PCSK1 form (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016). The cleavage of proPCSK1 that generates the 87 kDa PCSK1 is calcium-independent and occurs at a neutral pH. PCSK1 is sorted after to immature secretory granules where is activated by a cleavages at the C-terminal area and generates the 74 and 66kDa active forms. The active forms are than accumulated in dense-core secretory granules prior secretion.
Expression PCSK1 is expressed in the neuroendocrine system such as brain, adrenal glands and in endocrine cells of the small intestine (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016). Weak expression of PCSK1 is detected in adipocytes, α-cells of the pancreatic islets and certain types of immune cells. In brain, PC1 is mainly expressed in the hypothalamus (Dong W et al , 1997), but it is also found in cerebral cortex (Figure 3), hippocampus, and cerebellum (Billova S1, ET AL , 2007, Schäfer MK1, et al 1993). PC1/3 is also expressed in the adrenal medulla, pituitary, thyroid gland (Scopsi L et al. 1995, Day R ET AL 1992), endocrine pancreas (β-cells), liver and small intestine; including L and K cells (Tanaka S ET AL 1996). At low levels, PC1/3 was also detected in adipocytes (Min SYet al, 2016), in pancreatic islets (Itoh Y1, et al 1996), and in certain types of immune cells (LaMendolaet al 1997, Vindrola O et al 1994).
  Figure 3. Example of PCSK1 expression in the cerebral cortex and liver. Shown are overviews of stained tissues (circle) with high magnification of representative region (square). Adapted from Protein Atlas database.
Localisation In neuroendocrine cells, PCSK1 is mainly localized to the secretion granules and traffics within the regulated secretory pathway (Hornby PJ et al 1993, Malide D et al 1995). In macrophages PC1/3 is retained at the TGN as a pool that traffics to LAMP- related vesicles. PC1 vesicules are mostly detected during macrophages activation (Gagnon H et al, 2013)
Function PCSK1 cleaves protein precursors at the consensus motif (K/R)-Xn-(K/R)↓, with n=0, 2, 4 or 6, and X=any amino acids except Cys, to release mature proteins. PCSK1 favors cleavage after K/R motif, but is also able to cleave after other dibasic residues. PCSK1 often collaborates with PCSK2 to cleave substrates, such as neuropeptides and peptide hormones and its activity can be inhibited by the endogenous inhibitor proSAAS. PC1/3 gene disruption results in various developmental abnormalities' (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016) and PC1/3 null mice exhibit growth retardation (reviewed in Scamuffa N et al, 2006). The adult mutant mice are 60% of the normal size and show similarities with mice having mutant growth hormone releasing hormone ( GHRH) receptor ( GHRHR). Further analysis indicated that insulin-like growth factor-1 ( IGF1) and GHRH levels were significantly decreased in these mice; that may explain the observed growth retardation. PCSK1 null mice process normally pituitary POMC to ACTH and have normal levels of blood corticosterone. Like PCSK2 null mice, PCSK1 null mice also develop hyperproinsulinemia. These mice maintain normal glucose (Glc) tolerance in response to injection of glucose, suggesting that their hyperproinsulinemia does not impair their glucose homeostasis. Previously, Jackson et al. (reviewed in Scamuffa N et al, 2006) reported a human case of PC1/3 deficiency. The latter is due to PCSK1 gene mutation that prevents activation and secretion of proPC1/3 from the endoplasmic reticulum. The patient showed neonatal obesity. Subsequent studies revealed the presence of various endocrine defects, including the presence of very high circulating levels of proinsulin and multiple forms of partially processed POMC [ACTH precursors intermediate], low-serum estradiol, follicle-stimulating hormone, and LH. In 2003, another PCSK1 deficiency female subject was reported. In addition to the shared phenotypes with the previous subject, this female infant presented severe diarrhea, which started on the third postnatal day. Metabolic studies revealed a defect in the absorption of monosaccharides and fat, revealing the role of PC1/3 in the small intestinal absorptive function. Although the phenotypes of the PCSK1 null mice differ from those observed in these patients (PCSK1 null mice are not obese), the findings confirmed the importance of PCSK1 as a key neuroendocrine convertase (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016).
Homology An important paralog of this gene is PCSK2. Analysis of PCSK1 structure revealed that PCSK1 catalytic domain present a low percentage of homology with those of the other PCs (only 39% between PCSK1 and FURIN). The PCSK1 prodomain is formed by 83 residues and is highly conserved between orthologs (∼80% of sequence identity), although is not well conserved among paralogs of the convertase family (∼30-40%). The catalytic domain of PC1/3 is formed by 343 residues and is the most conserved region among proproteine convertases family members, with 50-60% sequence similarity. The P domain is a well-conserved region in PCs of approximately 150 residues and the Arg526-Arg-Gly-Asp529 (RRGD motif) is crucial for proper proPC1/3 processing and sorting to the secretory granules (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016). The C-terminus of PCSK1 with 159 aa is involved in the sorting processes to the dense core secretory granules, as well as in PCSK1 activity and stability ((reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016).


Germinal Various mutations were reported for human PCSK1 gene and were associated with various syndromes including obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016).

Implicated in

Entity Breast cancer
Note PC1 is highly elevated in human breast carcinomas (Cheng et al.1997). Stable expression of PC1 in human breast cancer cells MCF-7 altered their growth rate and response to estrogen and anti-estrogen treatments (Cheng et al. 2001). The use of transgenic mouse model revealed that PCSK1 expression promote normal and neoplastic mammary development and growth (Blanchard A et al 2009).
Entity Colon cancer and colon cancer metastasis
Note PC1 expression and protein cleavage profiles are altered in colon cancer and liver colorectal metastasis, compared to unaffected and normal liver. Active PCSK1 protein is overexpressed in these tumors and was found to correlate with the mRNA profiles (Tzimas G, et al 2005)
Entity Neuroendocrine tumors
Note High expression of PCSK1 is reported for neural and/or endocrine phenotype (Takumi I et al 1998, Jin L et al, 1999, Kajiwara H et al. 1999). However the role and prognostic value of PCSK1 in endocrine-related cancers is still unclear.
Entity Endocrine disorders
Note PCSK1 deficiency is a very rare genetic disorder, few patient cases have been reported. In human, the lack of PCSK1 was reported to be associated with several cases of hypogonadotropic and/or hypogonadism (O'Rahilly et al, 1995). Several patients showed low serum estradiol, FSH, and LH (Jackson R et al 1997, Martèn MG et al 2013, Bandsma RH, et al 2013, Wilschanski ET AL 2014, Solorzano-Vargas RS et al 2013).


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PMID 11081197
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This paper should be referenced as such :
Batrice Demoures, Graldine Siegfried, Abdel-Majid Khatib
PCSK1 (proprotein convertase subtilisin/kexin type 1)
Atlas Genet Cytogenet Oncol Haematol. 2018;22(6):236-241.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)PCSK1   8743
Entrez_Gene (NCBI)PCSK1    proprotein convertase subtilisin/kexin type 1
AliasesBMIQ12; NEC1; PC1; PC3; 
GeneCards (Weizmann)PCSK1
Ensembl hg19 (Hinxton)ENSG00000175426 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000175426 [Gene_View]  ENSG00000175426 [Sequence]  chr5:96390336-96432159 [Contig_View]  PCSK1 [Vega]
ICGC DataPortalENSG00000175426
TCGA cBioPortalPCSK1
Genatlas (Paris)PCSK1
SOURCE (Princeton)PCSK1
Genetics Home Reference (NIH)PCSK1
Genomic and cartography
GoldenPath hg38 (UCSC)PCSK1  -     chr5:96390336-96432159 -  5q15   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PCSK1  -     5q15   [Description]    (hg19-Feb_2009)
GoldenPathPCSK1 - 5q15 [CytoView hg19]  PCSK1 - 5q15 [CytoView hg38]
Genome Data Viewer NCBIPCSK1 [Mapview hg19]  
OMIM162150   600955   612362   
Gene and transcription
Genbank (Entrez)AB208874 AK303888 AK308575 BC031211 BC130295
RefSeq transcript (Entrez)NM_000439 NM_001177875 NM_001177876
Consensus coding sequences : CCDS (NCBI)PCSK1
Gene ExpressionPCSK1 [ NCBI-GEO ]   PCSK1 [ EBI - ARRAY_EXPRESS ]   PCSK1 [ SEEK ]   PCSK1 [ MEM ]
Gene Expression Viewer (FireBrowse)PCSK1 [ Firebrowse - Broad ]
GenevisibleExpression of PCSK1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5122
GTEX Portal (Tissue expression)PCSK1
Human Protein AtlasENSG00000175426-PCSK1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP29120   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP29120  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP29120
Catalytic activity : Enzyme3.4.21.93 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
Domaine pattern : Prosite (Expaxy)P_HOMO_B (PS51829)    SUBTILASE (PS51892)    SUBTILASE_ASP (PS00136)    SUBTILASE_HIS (PS00137)    SUBTILASE_SER (PS00138)   
Domains : Interpro (EBI)Galactose-bd-like_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    Proho_convert    S8_pro-domain    S8_pro-domain_sf   
Domain families : Pfam (Sanger)P_proprotein (PF01483)    Peptidase_S8 (PF00082)    Proho_convert (PF12177)    S8_pro-domain (PF16470)   
Domain families : Pfam (NCBI)pfam01483    pfam00082    pfam12177    pfam16470   
Conserved Domain (NCBI)PCSK1
AlphaFold pdb e-kbP29120   
Human Protein Atlas [tissue]ENSG00000175426-PCSK1 [tissue]
Protein Interaction databases
IntAct (EBI)P29120
Ontologies - Pathways
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular space  extracellular space  proteolysis  cell-cell signaling  membrane  protein processing  peptide hormone processing  peptide hormone processing  transport vesicle  secretory granule lumen  identical protein binding  neuron projection  peptide biosynthetic process  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular space  extracellular space  proteolysis  cell-cell signaling  membrane  protein processing  peptide hormone processing  peptide hormone processing  transport vesicle  secretory granule lumen  identical protein binding  neuron projection  peptide biosynthetic process  
REACTOMEP29120 [protein]
REACTOME PathwaysR-HSA-422085 [pathway]   
NDEx NetworkPCSK1
Atlas of Cancer Signalling NetworkPCSK1
Wikipedia pathwaysPCSK1
Orthology - Evolution
GeneTree (enSembl)ENSG00000175426
Phylogenetic Trees/Animal Genes : TreeFamPCSK1
Homologs : HomoloGenePCSK1
Homology/Alignments : Family Browser (UCSC)PCSK1
Gene fusions - Rearrangements
Fusion : QuiverPCSK1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPCSK1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PCSK1
Exome Variant ServerPCSK1
GNOMAD BrowserENSG00000175426
Varsome BrowserPCSK1
ACMGPCSK1 variants
Genomic Variants (DGV)PCSK1 [DGVbeta]
DECIPHERPCSK1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPCSK1 
ICGC Data PortalPCSK1 
TCGA Data PortalPCSK1 
Broad Tumor PortalPCSK1
OASIS PortalPCSK1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPCSK1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPCSK1
Mutations and Diseases : HGMDPCSK1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)PCSK1
DoCM (Curated mutations)PCSK1
CIViC (Clinical Interpretations of Variants in Cancer)PCSK1
NCG (London)PCSK1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM162150    600955    612362   
Genetic Testing Registry PCSK1
NextProtP29120 [Medical]
Target ValidationPCSK1
Huge Navigator PCSK1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDPCSK1
Pharm GKB GenePA33089
Clinical trialPCSK1
DataMed IndexPCSK1
PubMed122 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 Oct 8 21:24:41 CEST 2021

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