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PCSK9 - proprotein convertase subtilisin/kexin type 9 (human)

Gene
Symbol
Dates
  • Create:
    2016-09-14
  • Modify:
    2025-01-29
Description
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 autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
Enables several functions, including lipoprotein particle receptor binding activity; serine-type endopeptidase activity; and sodium channel inhibitor activity. Involved in several processes, including cholesterol homeostasis; low-density lipoprotein particle receptor catabolic process; and regulation of receptor-mediated endocytosis. Located in several cellular components, including endosome; lysosome; and perinuclear region of cytoplasm. Part of PCSK9-AnxA2 complex and PCSK9-LDLR complex. Implicated in familial hypercholesterolemia and hypobetalipoproteinemia.

The PCSK9 gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals.

The PCSK9 protein controls the number of low-density lipoprotein receptors, which are proteins on the surface of cells. These receptors play a critical role in regulating blood cholesterol levels. The receptors bind to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. Low-density lipoprotein receptors are particularly abundant in the liver, the organ responsible for removing most excess cholesterol from the body.

The number of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol is removed from the bloodstream. The PCSK9 protein breaks down low-density lipoprotein receptors before they reach the cell surface, so more cholesterol can remain in the bloodstream.

1 Names and Identifiers

1.1 Synonyms

  • FH3
  • FHCL3
  • HCHOLA3
  • LDLCQ1
  • NARC-1
  • NARC1
  • PC9
  • convertase subtilisin/kexin type 9 preproprotein
  • neural apoptosis regulated convertase 1
  • subtilisin/kexin-like protease PC9

1.1.1 MeSH Entry Terms

  • NARC-1 Protein
  • Neural Apoptosis-Regulated Convertase 1
  • Proprotein Convertase, Subtilisin-Kexin Type 9

1.2 Other Identifiers

1.2.1 HGNC ID

1.2.2 Ensembl ID

1.2.3 Alliance Gene ID

1.2.4 Bgee Gene ID

1.2.5 Enzyme Commission (EC) Number

1.2.6 GenCC ID

1.2.7 KEGG Gene

1.2.8 MIM Number

1.2.9 NCI Thesaurus Code

1.2.10 Open Targets ID

1.2.11 PharmGKB ID

1.2.12 Pharos Target

1.2.13 VEuPathDB ID

1.2.14 Wikidata

3 Proteins

3.1 Protein Function

Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PMID: 18039658). Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PMID: 17461796, PMID: 18197702, PMID: 18799458, PMID: 22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PMID: 18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.

3.2 Protein Isoforms

Isoform
Isoform 1
UniProt ID
RefSeq Accession
Isoform
Isoform 2
UniProt ID
RefSeq Accession

3.3 Protein 3D Structures

3.3.1 PDB Structures

3.3.2 NCBI Protein Structures

3.3.3 AlphaFold Structures

Highly accurate protein structure prediction with AlphaFold. Nature. 2021 Aug;596(7873):583-589. DOI:10.1038/s41586-021-03819-2. PMID:34265844; PMCID:PMC8371605

3.4 Protein Targets

4 Chemicals and Bioactivities

4.1 Tested Compounds

5 BioAssays

5.1 Small-Molecule BioAssays

5.2 RNAi BioAssays

6 Diseases and Phenotypes

6.1 GHR Health Conditions

6.2 KEGG Diseases

6.3 OMIM Phenotypes

6.4 MedGen Diseases

6.5 Gene-Disease Associations

7 Interactions and Pathways

7.1 Chemical-Gene Interactions

7.2 Interactions

7.3 Pathways

8 Expression

9 Target Development Level

10 Literature

10.1 Consolidated References

10.2 NLM Curated PubMed Citations

10.3 Gene-Chemical Co-Occurrences in Literature

10.4 Gene-Gene Co-Occurrences in Literature

10.5 Gene-Disease Co-Occurrences in Literature

11 Patents

11.1 Gene-Chemical Co-Occurrences in Patents

11.2 Gene-Gene Co-Occurrences in Patents

11.3 Gene-Disease Co-Occurrences in Patents

12 Classification

12.1 Gene Family

12.2 MeSH Tree

12.3 NCI Thesaurus Tree

12.4 Gene Ontology: Biological Process

12.5 Gene Ontology: Cellular Component

12.6 Gene Ontology: Molecular Function

12.7 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

12.8 ChEMBL Target Tree

13 Information Sources

  1. NCBI Gene
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    https://www.ncbi.nlm.nih.gov/home/about/policies/
  2. PubChem
  3. Medical Subject Headings (MeSH)
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  4. Alliance of Genome Resources
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    All annotations and data produced by Alliance members that are accessible from alliancegenome.org are distributed under a CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
    https://www.alliancegenome.org/privacy-warranty-licensing
  5. MedlinePlus Genetics
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    https://medlineplus.gov/about/using/usingcontent/
  6. BindingDB
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    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
  7. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  8. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  9. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  10. Therapeutic Target Database (TTD)
  11. BioGRID
    LICENSE
    The MIT License (MIT); Copyright Mike Tyers Lab
    https://wiki.thebiogrid.org/doku.php/terms_and_conditions
  12. Database of Interacting Proteins (DIP)
    LICENSE
    All DIP database records available under the terms set by the Creative Commons Attribution-NoDerivs License.
    https://dip.doe-mbi.ucla.edu/dip/termsofuse.html
  13. STRING: functional protein association networks
  14. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  15. Gene Curation Coalition (GenCC)
    LICENSE
    The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication.
    https://thegencc.org/terms.html
    PCSK9
  16. HUGO Gene Nomenclature Committee (HGNC)
    LICENSE
    No restrictions are imposed on access to, or use of, the data provided by the HGNC, which are provided to enhance knowledge and encourage progress in the scientific community.
    https://www.genenames.org/about/
  17. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
  18. NCBI Gene Expression Omnibus (GEO)
  19. NCBI MedGen
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    NCBI Website and Data Usage Policies and Disclaimers
    https://www.ncbi.nlm.nih.gov/home/about/policies/
  20. NCBI Structure
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    https://www.ncbi.nlm.nih.gov/home/about/policies/
  21. NCI Thesaurus (NCIt)
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    https://www.cancer.gov/policies/copyright-reuse
  22. Online Mendelian Inheritance in Man (OMIM)
    LICENSE
    The OMIM database is made available to the general public subject to certain restrictions.
    https://omim.org/help/copyright
  23. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  24. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  25. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  26. Swiss Institute of Bioinformatics Bgee
    LICENSE
    Creative Commons Zero license (CC0)
    https://www.bgee.org/about/
  27. UniProt
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    https://www.uniprot.org/help/license
  28. VEuPathDB: The Eukaryotic Pathogen, Vector and Host Informatics Resource
    LICENSE
    All data on VEuPathDB websites are provided freely for public use.
    https://veupathdb.org/veupathdb/app/static-content/about.html
  29. Wikidata
  30. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  31. Gene Ontology (GO)
    LICENSE
    Gene Ontology Consortium data and data products are licensed under the Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/legalcode)
    http://geneontology.org/docs/go-citation-policy/
  32. AlphaFold DB
    LICENSE
    All of the data provided is freely available for both academic and commercial use under Creative Commons Attribution 4.0 (CC-BY 4.0) licence terms.
    https://alphafold.ebi.ac.uk/faq
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