PCSK6 proprotein convertase subtilisin/kexin type 6 [Homo sapiens (human)] - Gene

Summary

Official Symbol: PCSK6provided by HGNC
Official Full Name: proprotein convertase subtilisin/kexin type 6provided by HGNC
Primary source: HGNC:HGNC:8569
See related: Ensembl:ENSG00000140479 MIM:167405; AllianceGenome:HGNC:8569
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: SPC4; PACE4
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 and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]
Expression: Biased expression in spleen (RPKM 31.3), liver (RPKM 30.7) and 12 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 15q26.3

Exon count:: 24

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	15	NC_000015.10 (101303933..101489707, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	15	NC_060939.1 (99058998..99244970, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	15	NC_000015.9 (101844138..102029910, complement)

Chromosome 15 - NC_000015.10 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?

PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.
Title: PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.
PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.
Title: PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.
PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer.
Title: PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer.
Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.
Title: Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.
Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.
Title: Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.
Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma.
Title: Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma.
Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors.
Title: Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors.
PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.
Title: PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.
PCSK6, a gene that has been implicated in the ontogenesis of bodily asymmetries by regulating the nodal cascade, is also relevant for structural asymmetries in the human brain.
Title: Structural Asymmetry in the Frontal and Temporal Lobes Is Associated with PCSK6 VNTR Polymorphism.
Data suggest that soluble corin lacking transmembrane domain is activated by PCSK6 in conditioned medium or in cell-free system but not intracellularly; cell membrane association is unnecessary for PCSK6 to activate corin; soluble corin and PCSK6 are secreted by cardiomyocytes (or HEK293 cells) via different intracellular pathways. (PCSK6 = proprotein convertase subtilisin/kexin type-6)
Title: Functional analysis of corin protein domains required for PCSK6-mediated activation.

Submit: New GeneRIF Correction See all GeneRIFs (40)

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
Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. EBI GWAS Catalog EBI GWAS CatalogPubMed
PCSK6 is associated with handedness in individuals with dyslexia. 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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Replication interactions

Interaction	Pubs
Knockdown of proprotein convertase subtilisin/kexin type 6 (PCSK6) by siRNA inhibits HIV-1 replication in HeLa P4/R5 cells	PubMed

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
Vpr	vpr	Vpr processing by soluble PCSK6 (PACE4) DOES NOT involve PAR1	PubMed
	vpr	soluble PCSK6 (PACE4) cleaves Vpr	PubMed
	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

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

RH70429 (e-PCR)
- UniSTS:56332

RH44602 (e-PCR)
- UniSTS:56077

GDB:455456 (e-PCR)
- UniSTS:157463

RH11158 (e-PCR)
- UniSTS:66850

PACE4_1021 (e-PCR)
- UniSTS:280884

SHGC-149807 (e-PCR)
- UniSTS:177232

STS-H73505 (e-PCR)
- UniSTS:74636

D16S325 (e-PCR)
- UniSTS:147089

D15S1284 (e-PCR)
- UniSTS:62901

RH1637 (e-PCR)
- UniSTS:4566

SGC35346 (e-PCR)
- UniSTS:19185

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables endopeptidase activity	IDA Inferred from Direct Assay more info	PubMed
enables endopeptidase activity	TAS Traceable Author Statement more info
enables heparin binding	IDA Inferred from Direct Assay more info	PubMed
enables nerve growth factor binding	IDA Inferred from Direct Assay 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 determination of left/right symmetry	IEA Inferred from Electronic Annotation more info
involved_in glycoprotein metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in nerve growth factor production	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
involved_in protein processing	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of BMP signaling pathway	TAS Traceable Author Statement more info	PubMed
involved_in secretion by cell	IDA Inferred from Direct Assay more info	PubMed
involved_in zygotic determination of anterior/posterior axis, embryo	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
located_in Golgi lumen	TAS Traceable Author Statement more info
is_active_in cell surface	IBA Inferred from Biological aspect of Ancestor more info
located_in cell surface	IDA Inferred from Direct Assay more info	PubMed
is_active_in collagen-containing extracellular matrix	IBA Inferred from Biological aspect of Ancestor more info
located_in collagen-containing extracellular matrix	IDA Inferred from Direct Assay more info	PubMed
located_in endoplasmic reticulum	IEA Inferred from Electronic Annotation more info
located_in extracellular region	TAS Traceable Author Statement more info
is_active_in extracellular space	IBA Inferred from Biological aspect of Ancestor more info
located_in extracellular space	IDA Inferred from Direct Assay more info	PubMed
is_active_in membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: proprotein convertase subtilisin/kexin type 6

Names: paired basic amino acid cleaving enzyme 4; paired basic amino acid cleaving system 4; subtilisin-like proprotein convertase 4; subtilisin/kexin-like protease PACE4

NP_001278238.1

EC 3.4.21.-

NP_002561.1

EC 3.4.21.-

NP_612192.1

EC 3.4.21.-

NP_612195.1

EC 3.4.21.-

NP_612196.1

EC 3.4.21.-

NP_612197.1

EC 3.4.21.-

NP_612198.2

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_030047.4 RefSeqGene

Range

40496..226270

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_888

mRNA and Protein(s)

NM_001291309.2 → NP_001278238.1 proprotein convertase subtilisin/kexin type 6 isoform i preproprotein

Status: REVIEWED

Description

Transcript Variant: This variant (9) lacks two consecutive exons in the central coding region but maintains reading frame, compared to variant 1. The encoded isoform (i) is shorter, compared to isoform PACE4-AI.

Source sequence(s)

AB208955, AM491522, BU732171, DB143095, M80482

UniProtKB/TrEMBL

Q59H04

Related

ENSP00000381246.2, ENST00000398185.6

Conserved Domains (7) summary

cd04059
Location:160 → 436

Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases

smart00261
Location:770 → 812

FU; Furin-like repeats

cd00064
Location:725 → 771

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:465 → 555

P_proprotein; Proprotein convertase P-domain

pfam08686
Location:868 → 891

PLAC; PLAC (protease and lacunin) domain

pfam14843
Location:620 → 730

GF_recep_IV; Growth factor receptor domain IV

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain
NM_002570.5 → NP_002561.1 proprotein convertase subtilisin/kexin type 6 isoform PACE4-AI preproprotein

See identical proteins and their annotated locations for NP_002561.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the predominant isoform (PACE4-AI, also known as PACE4 and PACE4-A).

Source sequence(s)

AL545278, AM491522, BU732171, BX428035, M80482

Consensus CDS

CCDS73790.1

UniProtKB/Swiss-Prot

P29122, Q15099, Q15100, Q9UEG7, Q9UEJ1, Q9UEJ2, Q9UEJ7, Q9UEJ8, Q9UEJ9, Q9Y4G9, Q9Y4H0, Q9Y4H1

UniProtKB/TrEMBL

A0A087WY68

Related

ENSP00000482760.1, ENST00000611716.5

Conserved Domains (8) summary

cd04059
Location:160 → 454

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

smart00261
Location:743 → 789

FU; Furin-like repeats

cd00064
Location:799 → 845

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:196 → 479

Peptidase_S8; Subtilase family

pfam01483
Location:539 → 629

P_proprotein; Proprotein convertase P-domain

pfam08686
Location:942 → 965

PLAC; PLAC (protease and lacunin) domain

pfam15913
Location:751 → 847

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

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain
NM_138319.4 → NP_612192.1 proprotein convertase subtilisin/kexin type 6 isoform PACE4-AII preproprotein

See identical proteins and their annotated locations for NP_612192.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate in-frame exon in the 3' coding region, compared to variant 1. The resulting isoform (PACE4-AII) is shorter but maintains the same reading frame, compared to isoform PACE4-AI.

Source sequence(s)

AL545278, AM491522, BU732171, BX428035, M80482

Consensus CDS

CCDS73789.1

UniProtKB/TrEMBL

A0A087WZR0

Related

ENSP00000479496.1, ENST00000618548.4

Conserved Domains (8) summary

cd04059
Location:160 → 454

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

smart00261
Location:730 → 776

FU; Furin-like repeats

cd00064
Location:786 → 832

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:196 → 479

Peptidase_S8; Subtilase family

pfam01483
Location:539 → 629

P_proprotein; Proprotein convertase P-domain

pfam08686
Location:929 → 952

PLAC; PLAC (protease and lacunin) domain

pfam15913
Location:738 → 834

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

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain
NM_138322.4 → NP_612195.1 proprotein convertase subtilisin/kexin type 6 isoform PACE4B preproprotein

See identical proteins and their annotated locations for NP_612195.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) has multiple differences in the coding region, one of which is a frameshift, compared to variant 1. The encoded isoform PACE4B (also known as PACE4.1) has a distinct C-terminus compared to isoform PACE4-AI. This isoform is thought to be catalytically inactive.

Source sequence(s)

AC087528, AM491522, HY122769, M80482

UniProtKB/Swiss-Prot

P29122

UniProtKB/TrEMBL

A2RQD9

Conserved Domains (3) summary

cd04059
Location:160 → 454

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

pfam00082
Location:196 → 455

Peptidase_S8; Subtilase family

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain
NM_138323.3 → NP_612196.1 proprotein convertase subtilisin/kexin type 6 isoform PACE4CS preproprotein

See identical proteins and their annotated locations for NP_612196.1

Status: REVIEWED

Description

Transcript Variant: This variant (5) uses an alternate exon in the 3' coding region and lacks several downstream exons when compared to variant 1. These differences cause a frameshift and thus isoform PACE4CS has a distinct C-terminus compared to isoform PACE4-AI.

Source sequence(s)

AC023024, AL545278, AM491522, BX428035, D28513, M80482

Consensus CDS

CCDS73791.1

UniProtKB/TrEMBL

H0YKZ4

Related

ENSP00000478081.1, ENST00000615296.4

Conserved Domains (4) summary

cd04059
Location:160 → 454

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

pfam00082
Location:196 → 455

Peptidase_S8; Subtilase family

pfam01483
Location:539 → 623

P_proprotein; Proprotein convertase P-domain

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain
NM_138324.3 → NP_612197.1 proprotein convertase subtilisin/kexin type 6 isoform PACE4C preproprotein

See identical proteins and their annotated locations for NP_612197.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) uses two alternate exons in the 3' coding region and lacks several downstream exons when compared to variant 1. These differences cause a frameshift and thus isoform PACE4C has a distinct C-terminus compared to isoform PACE4-AI.

Source sequence(s)

AC023024, AL545278, AM491522, BX428035, D28513, M80482

Consensus CDS

CCDS73793.1

UniProtKB/TrEMBL

H0YKZ4

Related

ENSP00000477768.1, ENST00000611967.4

Conserved Domains (4) summary

cd04059
Location:160 → 454

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

pfam00082
Location:196 → 479

Peptidase_S8; Subtilase family

pfam01483
Location:539 → 623

P_proprotein; Proprotein convertase P-domain

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain
NM_138325.4 → NP_612198.2 proprotein convertase subtilisin/kexin type 6 isoform f preproprotein

See identical proteins and their annotated locations for NP_612198.2

Status: REVIEWED

Description

Transcript Variant: This variant (6) lacks multiple 3' exons and uses an alternate 3' terminal exon, compared to variant 1. This results in a shorter isoform (f) that has a distinct C-terminus, compared to isoform PACE4-AI.

Source sequence(s)

AC023024, AL545278, AM491522, BX428035, D28514, HY205376, M80482

Consensus CDS

CCDS73792.1

UniProtKB/TrEMBL

H0YKZ4, H7BXT3

Related

ENSP00000332052.8, ENST00000331826.12

Conserved Domains (4) summary

cd04059
Location:160 → 454

Peptidases_S8_Protein_convertases_Kexins_Furin-like; Peptidase S8 family domain in Protein convertases

pfam00082
Location:196 → 479

Peptidase_S8; Subtilase family

pfam01483
Location:539 → 623

P_proprotein; Proprotein convertase P-domain

pfam16470
Location:73 → 149

S8_pro-domain; Peptidase S8 pro-domain

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_000015.10 Reference GRCh38.p14 Primary Assembly

Range

101303933..101489707 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

NC_060939.1 Alternate T2T-CHM13v2.0

Range

99058998..99244970 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

NM_138320.1: Suppressed sequence

Description

NM_138320.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.
NM_138321.1: Suppressed sequence

Description

NM_138321.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.