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

Gene ID: 5046, updated on 8-May-2016
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 HPRD:01329; MIM:167405; Vega:OTTHUMG00000172097
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]
Orthologs
Location:
15q26.3
Exon count:
24
Annotation release Status Assembly Chr Location
107 current GRCh38.p2 (GCF_000001405.28) 15 NC_000015.10 (101303928..101489984, complement)
105 previous assembly GRCh37.p13 (GCF_000001405.25) 15 NC_000015.9 (101844133..102030187, complement)

Chromosome 15 - NC_000015.10Genomic Context describing neighboring genes Neighboring gene VCP interacting membrane selenoprotein Neighboring gene small nuclear ribonucleoprotein polypeptide A' Neighboring gene uncharacterized LOC100507472 Neighboring gene uncharacterized LOC105371028 Neighboring gene small nuclear ribonucleoprotein polypeptide C pseudogene 18

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

NHGRI GWAS Catalog

Description
Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
NHGRI GWA Catalog
PCSK6 is associated with handedness in individuals with dyslexia.
NHGRI GWA Catalog

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 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

  • Developmental Biology, organism-specific biosystem (from REACTOME)
    Developmental Biology, organism-specific biosystemAs a first step towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of three kinds of processes have been annotated. These are a...
  • NGF processing, organism-specific biosystem (from REACTOME)
    NGF processing, organism-specific biosystemAll neurotrophins (NTs) are generated as pre-pro-neurotrophin precursors. The signal peptide is cleaved off as NT is associated with the endoplasmic reticulum (ER). The resulting pro-NT can form a ho...
  • Signal Transduction, organism-specific biosystem (from REACTOME)
    Signal Transduction, organism-specific biosystemSignal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such a...
  • Signaling by NODAL, organism-specific biosystem (from REACTOME)
    Signaling by NODAL, organism-specific biosystemSignaling by NODAL is essential for patterning of the axes of the embryo and formation of mesoderm and endoderm (reviewed in Schier 2009, Shen 2007). The NODAL proprotein is secreted and cleaved extr...
  • Signalling by NGF, organism-specific biosystem (from REACTOME)
    Signalling by NGF, organism-specific biosystemNeurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in mi...
Products Interactant Other Gene Complex Source Pubs Description

Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
endopeptidase activity IDA
Inferred from Direct Assay
more info
PubMed 
heparin binding IDA
Inferred from Direct Assay
more info
PubMed 
nerve growth factor binding IDA
Inferred from Direct Assay
more info
PubMed 
serine-type endopeptidase activity IDA
Inferred from Direct Assay
more info
PubMed 
Process Evidence Code Pubs
determination of left/right symmetry IEA
Inferred from Electronic Annotation
more info
 
glycoprotein metabolic process IDA
Inferred from Direct Assay
more info
PubMed 
nerve growth factor processing TAS
Traceable Author Statement
more info
 
nerve growth factor production IDA
Inferred from Direct Assay
more info
PubMed 
peptide hormone processing IDA
Inferred from Direct Assay
more info
PubMed 
protein processing IDA
Inferred from Direct Assay
more info
PubMed 
regulation of BMP signaling pathway TAS
Traceable Author Statement
more info
PubMed 
secretion by cell IDA
Inferred from Direct Assay
more info
PubMed 
zygotic determination of anterior/posterior axis, embryo IEA
Inferred from Electronic Annotation
more info
 
Component Evidence Code Pubs
Golgi lumen TAS
Traceable Author Statement
more info
 
cell surface IDA
Inferred from Direct Assay
more info
PubMed 
endoplasmic reticulum IEA
Inferred from Electronic Annotation
more info
 
extracellular matrix IDA
Inferred from Direct Assay
more info
PubMed 
extracellular space IDA
Inferred from Direct Assay
more info
PubMed 
membrane IEA
Inferred from Electronic Annotation
more info
 
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

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

  1. NG_030047.3 RefSeqGene

    Range
    40219..226275
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001291309.1NP_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, AC087528, AM491522, BU732171, DB143095, M80482
    UniProtKB/Swiss-Prot
    P29122
    UniProtKB/TrEMBL
    A2RQD9, Q59H04
    Related
    ENSP00000381246, OTTHUMP00000247640, ENST00000398185, OTTHUMT00000416830
    Conserved Domains (6) summary
    cd04059
    Location:160436
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    smart00261
    Location:822856
    FU; Furin-like repeats
    cd00064
    Location:675724
    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:200453
    Peptidase_S8; Subtilase family
    pfam01483
    Location:465555
    P_proprotein; Proprotein convertase P-domain
    pfam08686
    Location:861893
    PLAC; PLAC (protease and lacunin) domain
  2. NM_002570.4NP_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)
    AC087528, AL545278, AM491522, BU732171, BX428035, M80482
    Consensus CDS
    CCDS73790.1
    UniProtKB/Swiss-Prot
    P29122
    UniProtKB/TrEMBL
    A2RQD9
    Related
    ENSP00000482760, OTTHUMP00000276431, ENST00000611716, OTTHUMT00000416811
    Conserved Domains (6) summary
    cd04059
    Location:160454
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    smart00261
    Location:896930
    FU; Furin-like repeats
    cd00064
    Location:749798
    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:200481
    Peptidase_S8; Subtilase family
    pfam01483
    Location:539629
    P_proprotein; Proprotein convertase P-domain
    pfam08686
    Location:935967
    PLAC; PLAC (protease and lacunin) domain
  3. NM_138319.3NP_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)
    AC087528, AL545278, AM491522, BU732171, BX428035, M80482
    Consensus CDS
    CCDS73789.1
    UniProtKB/Swiss-Prot
    P29122
    UniProtKB/TrEMBL
    A2RQD9
    Related
    ENSP00000479496, OTTHUMP00000276432, ENST00000618548, OTTHUMT00000416814
    Conserved Domains (6) summary
    cd04059
    Location:160454
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    smart00261
    Location:883917
    FU; Furin-like repeats
    cd00064
    Location:736785
    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:200481
    Peptidase_S8; Subtilase family
    pfam01483
    Location:539629
    P_proprotein; Proprotein convertase P-domain
    pfam08686
    Location:922954
    PLAC; PLAC (protease and lacunin) domain
  4. NM_138322.3NP_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 (2) summary
    cd04059
    Location:160454
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    pfam00082
    Location:200455
    Peptidase_S8; Subtilase family
  5. NM_138323.2NP_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, AC087528, AL545278, AM491522, BX428035, D28513, M80482
    Consensus CDS
    CCDS73791.1
    UniProtKB/Swiss-Prot
    P29122
    UniProtKB/TrEMBL
    A2RQD9
    Related
    ENSP00000478081, OTTHUMP00000276436, ENST00000615296, OTTHUMT00000416899
    Conserved Domains (3) summary
    cd04059
    Location:160454
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    pfam00082
    Location:200481
    Peptidase_S8; Subtilase family
    pfam01483
    Location:539623
    P_proprotein; Proprotein convertase P-domain
  6. NM_138324.2NP_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, AC087528, AL545278, AM491522, BX428035, D28513, M80482
    Consensus CDS
    CCDS73793.1
    UniProtKB/Swiss-Prot
    P29122
    UniProtKB/TrEMBL
    A2RQD9
    Related
    ENSP00000477768, OTTHUMP00000276435, ENST00000611967, OTTHUMT00000416813
    Conserved Domains (3) summary
    cd04059
    Location:160454
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    pfam00082
    Location:200481
    Peptidase_S8; Subtilase family
    pfam01483
    Location:539622
    P_proprotein; Proprotein convertase P-domain
  7. NM_138325.3NP_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, AC087528, AL545278, AM491522, BX428035, D28514, HY205376, M80482
    Consensus CDS
    CCDS73792.1
    UniProtKB/Swiss-Prot
    P29122
    UniProtKB/TrEMBL
    A2RQD9, H7BXT3
    Related
    ENSP00000332052, ENST00000331826
    Conserved Domains (3) summary
    cd04059
    Location:160454
    Peptidases_S8_Protein_convertases_Kexins_Furin-lik; Peptidase S8 family domain in Protein convertases
    pfam00082
    Location:200481
    Peptidase_S8; Subtilase family
    pfam01483
    Location:539622
    P_proprotein; Proprotein convertase P-domain

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 107 details...

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

Reference GRCh38.p2 Primary Assembly

Genomic

  1. NC_000015.10 Reference GRCh38.p2 Primary Assembly

    Range
    101303928..101489984 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.1

Genomic

  1. NC_018926.2 Alternate CHM1_1.1

    Range
    101685119..101871305 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

  1. 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.
  2. 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.