Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

PCSK9 (Q8NBP7) - Overview - Molecular Target Synopsis

Protein


PCSK9, Proprotein convertase subtilisin/kexin type 9
Enzyme Classification 3.4.21.-
UniProt Q8NBP7

Also Known as PCSK9_HUMAN, PCSK9, NARC1

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 (PubMed: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 (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed: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 (PubMed: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. Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR (PubMed:18799458).

6E4Z
13 RESIDUE FRAGMENT OF
PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9
IN THE STRUCTURE OF
ANTI-PCSK9 FAB 6E2 BOUND TO THE MODIFIED N-TERMINAL PEPTIDE FROM PCSK9
RCSB/PDB
Inspect Structure
See all 3D Structures for PCSK9

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


Gene Copy Number Variation


In COSMIC - Cell Lines Project PCSK9 has gain in 3 cell-lines, loss in 2 cell-lines and no signal in 1000 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: KM12, COLO205, K_562

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H2073, SNU-1, COLO 205

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HMEC, K562, HeLa-S3

(see details)

3D Structures


For PCSK9 there are:
32 structures (59 chains) solved
5 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


PCSK9 has been screened with 4 compounds (10 bioactivities). (see details)