PCSK5 proprotein convertase subtilisin/kexin type 5 [Homo sapiens (human)] - Gene

Summary

Official Symbol: PCSK5provided by HGNC
Official Full Name: proprotein convertase subtilisin/kexin type 5provided by HGNC
Primary source: HGNC:HGNC:8747
See related: Ensembl:ENSG00000099139 MIM:600488; AllianceGenome:HGNC:8747
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PC5; PC6; PC6A; SPC6
Summary: This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein 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. This encoded protein is widely expressed and one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It mediates posttranslational endoproteolytic processing for several integrin alpha subunits and is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160. Alternative splicing results in multiple transcript variants, some of which encode distinct isoforms, including a protease packaged into dense core granules (PC5A) and a type 1 membrane bound protease (PC5B). [provided by RefSeq, May 2014]
Expression: Broad expression in small intestine (RPKM 6.4), duodenum (RPKM 5.8) and 20 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 9q21.13

Exon count:: 42

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	9	NC_000009.12 (75889809..76362975)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	9	NC_060933.1 (88048502..88519580)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	9	NC_000009.11 (78505589..78977891)

Chromosome 9 - NC_000009.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease.
Title: Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease.
this study demonstrates that Pcsk5 is expressed in bone-forming cells, and that OPN is a novel substrate for PC5/6
Title: Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone.
loss of the convertase furin or PC5/6 in hepatocytes results in a approximately 30% decrease in APC levels, with no significant contribution from PACE4. We conclude that prior convertase cleavage of protein C in hepatocytes is critical for its thrombin activation.
Title: Thrombin activation of protein C requires prior processing by a liver proprotein convertase.
Case Report: whole exome sequencing of a case with the VACTERL association uncovered a novel frameshift mutation in the PCSK5 gene.
Title: PCSK5 mutation in a patient with the VACTERL association.
full-length alpha-DG in the human endometrial epithelium is a barrier for embryo attachment and that removal of alpha-DG-N by proprotein convertase 5/6 (PC6; a protease critical for implantation
Title: Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women.
Proprotein convertase 5/6 cleaves PDGFA in the human endometrium in preparation for embryo implantation.
Title: Proprotein convertase 5/6 cleaves platelet-derived growth factor A in the human endometrium in preparation for embryo implantation.
PC5/6A is involved in squamous differentiation of human nasal epithelial cells, possibly through up-regulation of the BMP-2 signaling pathway.
Title: Proprotein convertase 5/6a is associated with bone morphogenetic protein-2-induced squamous cell differentiation.
overexpression of PCs, furin and PC5, but not PC7, which are all expressed in SMC, increase PKGI cleavage in a dose-dependent manner
Title: Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport.
study implicates PC6 as a key regulatory protein essential for the attachment of the blastocyst to the endometrial epithelium through the processing of pro-integrin-alphas
Title: Cleavage of endometrial α-integrins into their functional forms is mediated by proprotein convertase 5/6.
PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization.
Title: Proprotein convertase 5/6 is critical for embryo implantation in women: regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions.

Submit: New GeneRIF Correction See all GeneRIFs (29)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. EBI GWAS Catalog EBI GWAS CatalogPubMed
Hundreds of variants clustered in genomic loci and biological pathways affect human height. EBI GWAS Catalog EBI GWAS CatalogPubMed
Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp160, precursor	env	Kexin/subtilisin-related convertases such as furin, PACE4, PC1, PC2, PC5 and its isoform PC5/6-B can process HIV-1 gp160 to gp120/gp41	PubMed
Tat	tat	Microarray analysis indicates HIV-1 Tat-induced upregulation of proprotein convertase subtilisin/kexin type 5 (PCSK5) in primary human brain microvascular endothelial cells	PubMed
	tat	Proprotein convertase subtilisin/kexin type 5 (PCSK5) is upregulated in HIV-1 Tat and NC cotransfection of HEK 293T cells	PubMed
Vpr	vpr	Proprotein convertase PC5 cleaves extracellular HIV-1 Vpr between amino-acids 88-89 located within the functionally important C-terminal arginine-rich domain RQRR(88)V/A/G(89)R in Vpr	PubMed
nucleocapsid	gag	Proprotein convertase subtilisin/kexin type 5 (PCSK5) is upregulated in HIV-1 Tat and NC cotransfection of HEK 293T cells	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D9S276 (e-PCR)
- UniSTS:83980

G35008 (e-PCR)
- UniSTS:78621

SHGC-146362 (e-PCR)
- UniSTS:175172

SHGC-148548 (e-PCR)
- UniSTS:176456

SHGC-148973 (e-PCR)
- UniSTS:176713

RH122958 (e-PCR)
- UniSTS:135255

SHGC-37380 (e-PCR)
- UniSTS:14423

D9S1807 (e-PCR), detects polymorphism
- UniSTS:41310

RH48203 (e-PCR)
- UniSTS:76922

SHGC-142784 (e-PCR)
- UniSTS:171657

D9S1974 (e-PCR)
- UniSTS:61581

SHGC-146910 (e-PCR)
- UniSTS:175505

SHGC-155149 (e-PCR)
- UniSTS:184979

L17877 (e-PCR)
- UniSTS:61334

D9S276 (e-PCR)
- UniSTS:35488

RH123466 (e-PCR)
- UniSTS:135854

D9S1997 (e-PCR)
- UniSTS:69564

SHGC-32247 (e-PCR)
- UniSTS:55237

G34998 (e-PCR)
- UniSTS:10464

WI-15571 (e-PCR)
- UniSTS:5604

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables endopeptidase activity	EXP Inferred from Experiment more info	PubMed
enables peptidase activity	IDA Inferred from Direct Assay more info	PubMed
enables peptide binding	ISS Inferred from Sequence or Structural Similarity more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables serine-type endopeptidase activity	IBA Inferred from Biological aspect of Ancestor more info
enables serine-type endopeptidase activity	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in anterior/posterior pattern specification	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cell-cell signaling	TAS Traceable Author Statement more info	PubMed
involved_in cytokine precursor processing	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in embryo implantation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in embryonic digestive tract development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in embryonic digestive tract development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in embryonic skeletal system development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in embryonic skeletal system development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in heart development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in kidney development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in kidney development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in limb morphogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in peptide biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in peptide hormone processing	IBA Inferred from Biological aspect of Ancestor more info
involved_in peptide hormone processing	IDA Inferred from Direct Assay more info	PubMed
involved_in plasma lipoprotein particle remodeling	TAS Traceable Author Statement more info
acts_upstream_of_or_within protein processing	IDA Inferred from Direct Assay more info	PubMed
involved_in protein processing	IDA Inferred from Direct Assay more info	PubMed
involved_in renin secretion into blood stream	IEP Inferred from Expression Pattern more info	PubMed
involved_in respiratory tube development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in signal peptide processing	IDA Inferred from Direct Assay more info	PubMed
involved_in viral life cycle	IEP Inferred from Expression Pattern more info	PubMed
involved_in viral life cycle	ISS Inferred from Sequence or Structural Similarity more info	PubMed

Component	Evidence Code	Pubs
located_in Golgi apparatus	IDA Inferred from Direct Assay more info
located_in Golgi apparatus	TAS Traceable Author Statement more info	PubMed
located_in Golgi lumen	TAS Traceable Author Statement more info
is_active_in Golgi membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in extracellular region	TAS Traceable Author Statement more info
located_in extracellular space	ISS Inferred from Sequence or Structural Similarity more info	PubMed
is_active_in trans-Golgi network	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: proprotein convertase subtilisin/kexin type 5

Names: prohormone convertase 5; proprotein convertase 6; protease PC6; subtilase; subtilisin/kexin-like protease PC5

NP_001177411.1

EC 3.4.21.-

NP_001358972.1

EC 3.4.21.-

NP_006191.2

EC 3.4.21.-

XP_011517071.1

EC 3.4.21.-

XP_011517072.1

EC 3.4.21.-

XP_047279410.1

EC 3.4.21.-

XP_047279411.1

EC 3.4.21.-

XP_047279412.1

EC 3.4.21.-

XP_054219050.1

EC 3.4.21.-

XP_054219051.1

EC 3.4.21.-

XP_054219052.1

EC 3.4.21.-

XP_054219053.1

EC 3.4.21.-

XP_054219054.1

EC 3.4.21.-

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_029445.1 RefSeqGene

Range

5030..477332

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001190482.2 → NP_001177411.1 proprotein convertase subtilisin/kexin type 5 isoform PC6B preproprotein

See identical proteins and their annotated locations for NP_001177411.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes isoform PC5B, alternatively referred to as the long form.

Source sequence(s)

AK122718, AL391868, AL589653, BC012064, DA992221, DT932737, DV080167, DY655633

Consensus CDS

CCDS55320.1

UniProtKB/Swiss-Prot

F5H2G7, Q13527, Q92824, Q96EP4

UniProtKB/TrEMBL

Q5JSG7

Related

ENSP00000446280.1, ENST00000545128.5

Conserved Domains (8) summary

cd04059
Location:126 → 420

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

smart00261
Location:782 → 823

FU; Furin-like repeats

cd00064
Location:1470 → 1518

FU; Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

pfam00082
Location:162 → 445

Peptidase_S8; Subtilase family

pfam00757
Location:845 → 992

Furin-like; Furin-like cysteine rich region

pfam01483
Location:505 → 595

P_proprotein; Proprotein convertase P-domain

pfam14843
Location:1569 → 1686

GF_recep_IV; Growth factor receptor domain IV

pfam16470
Location:38 → 114

S8_pro-domain; Peptidase S8 pro-domain
NM_001372043.1 → NP_001358972.1 proprotein convertase subtilisin/kexin type 5 isoform 3 precursor

Status: REVIEWED

Source sequence(s)

AL353607, AL359253, AL391868, AL589653

Consensus CDS

CCDS94423.1

UniProtKB/TrEMBL

A0A669KA35, Q5JSG7

Related

ENSP00000500971.1, ENST00000674117.1

Conserved Domains (7) summary

pfam03302
Location:724 → 1100

VSP; Giardia variant-specific surface protein

cd04059
Location:126 → 420

Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases

smart00261
Location:1126 → 1162

FU; Furin-like repeats

cd00064
Location:1209 → 1256

FU; Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

pfam01483
Location:505 → 595

P_proprotein; Proprotein convertase P-domain

pfam14843
Location:635 → 744

GF_recep_IV; Growth factor receptor domain IV

pfam16470
Location:38 → 114

S8_pro-domain; Peptidase S8 pro-domain
NM_006200.6 → NP_006191.2 proprotein convertase subtilisin/kexin type 5 isoform PC6A preproprotein

See identical proteins and their annotated locations for NP_006191.2

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks several 3' exons but contains an alternate 3' terminal exon, and it thus differs in the 3' coding region and 3' UTR, compared to variant 1. The resulting isoform (PC5A, alternatively referred to as the short form) has a substantially shorter and distinct C-terminus, compared to isoform PC5B.

Source sequence(s)

AI379031, AK023096, BC012064, BM719207, CK023649, CN360310, DA992221, HY155058

Consensus CDS

CCDS6652.1

UniProtKB/Swiss-Prot

Q92824

Related

ENSP00000365943.4, ENST00000376752.9

Conserved Domains (6) summary

cd04059
Location:126 → 420

Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases

smart00261
Location:782 → 823

FU; Furin-like repeats

pfam01483
Location:505 → 595

P_proprotein; Proprotein convertase P-domain

pfam08686
Location:873 → 910

PLAC; PLAC (protease and lacunin) domain

pfam14843
Location:635 → 744

GF_recep_IV; Growth factor receptor domain IV

pfam16470
Location:38 → 114

S8_pro-domain; Peptidase S8 pro-domain

RNA

NR_120409.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate exon in the central region, and also lacks several 3' exons but contains an alternate 3' terminal exon, compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AI379031, AK023096, AK225773, BM719207, CK023649, CN360310, DA992221, HY155058

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000009.12 Reference GRCh38.p14 Primary Assembly

Range

75889809..76362975

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047423454.1 → XP_047279410.1 proprotein convertase subtilisin/kexin type 5 isoform X2
XM_011518769.4 → XP_011517071.1 proprotein convertase subtilisin/kexin type 5 isoform X1

UniProtKB/TrEMBL

Q5JSG7

Conserved Domains (9) summary

cd04059
Location:126 → 420

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

smart00261
Location:782 → 823

FU; Furin-like repeats

cd00064
Location:1496 → 1544

FU; Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

pfam00082
Location:162 → 445

Peptidase_S8; Subtilase family

pfam00757
Location:845 → 992

Furin-like; Furin-like cysteine rich region

pfam01483
Location:505 → 595

P_proprotein; Proprotein convertase P-domain

pfam14843
Location:1595 → 1712

GF_recep_IV; Growth factor receptor domain IV

pfam15913
Location:1236 → 1304

Furin-like_2; Furin-like repeat, cysteine-rich

pfam16470
Location:38 → 114

S8_pro-domain; Peptidase S8 pro-domain
XM_047423455.1 → XP_047279411.1 proprotein convertase subtilisin/kexin type 5 isoform X4
XM_047423456.1 → XP_047279412.1 proprotein convertase subtilisin/kexin type 5 isoform X5
XM_011518770.3 → XP_011517072.1 proprotein convertase subtilisin/kexin type 5 isoform X3

UniProtKB/TrEMBL

Q5JSG7

Related

ENSP00000411654.1, ENST00000424854.6

Conserved Domains (7) summary

pfam03302
Location:845 → 1130

VSP; Giardia variant-specific surface protein

smart00261
Location:336 → 377

FU; Furin-like repeats

cd00064
Location:1051 → 1099

FU; Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

pfam00757
Location:399 → 546

Furin-like; Furin-like cysteine rich region

pfam01483
Location:59 → 149

P_proprotein; Proprotein convertase P-domain

pfam14843
Location:1150 → 1267

GF_recep_IV; Growth factor receptor domain IV

pfam15913
Location:791 → 859

Furin-like_2; Furin-like repeat, cysteine-rich

Alternate T2T-CHM13v2.0

Genomic

NC_060933.1 Alternate T2T-CHM13v2.0

Range

88048502..88519580

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054363076.1 → XP_054219051.1 proprotein convertase subtilisin/kexin type 5 isoform X2
XM_054363075.1 → XP_054219050.1 proprotein convertase subtilisin/kexin type 5 isoform X1
XM_054363078.1 → XP_054219053.1 proprotein convertase subtilisin/kexin type 5 isoform X4
XM_054363079.1 → XP_054219054.1 proprotein convertase subtilisin/kexin type 5 isoform X5
XM_054363077.1 → XP_054219052.1 proprotein convertase subtilisin/kexin type 5 isoform X3