Protein / target
Proprotein convertase subtilisin/kexin type 9
Protein at a glance
Biological role
Very-low-density lipoprotein particle receptor binding
Primary system
Endocrine & metabolic
Strongest disease association
hypercholesterolemia, autosomal dominant, 3
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
4 approved · 6 in clinical development
Research activity
Actively researched
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
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 (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:17461796, PubMed:18197702, PubMed:18799458, 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
Subcellular location
Domains and Gene Ontology detail (53)Hide
Domains & features
Gene Ontology
- Ccell surface
- CCOPII-coated ER to Golgi transport vesicle
- Ccytoplasm
- Cearly endosome
- Cendolysosome membrane
- Cendoplasmic reticulum
- Cendoplasmic reticulum lumen
- Cextracellular region
- Cextracellular space
- Cextrinsic component of external side of plasma membrane
- CGolgi apparatus
- Clate endosome
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Apoptosis & cell death
- ·apoptotic process
- ·positive regulation of neuron apoptotic process
- ·regulation of neuron apoptotic process
Proteolysis
- ·endopeptidase activity
- ·serine-type endopeptidase activity
Kinase signalling
- ·Post-translational protein phosphorylation
Metabolic enzyme activity
- ·cholesterol metabolic process
View underlying pathways (4)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
Subtilisin/kexin type 9 inhibitor
Appears in clinical studies involving familial hypercholesterolemia, coronary artery disorder, Hypercholesterolemia, cardiovascular disorder
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Strongest genetic associations
Human genetic evidence — the most direct causal link between this target and a disease.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 959 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 10 total
chronic obstructive pulmonary disease · hyperlipidemia · familial hypercholesterolemia
familial hypercholesterolemia · cardiovascular disorder · familial hypercholesterolemia
Combined hyperlipidemia · familial hypercholesterolemia · colorectal cancer
familial hypercholesterolemia · Hypercholesterolemia · Combined hyperlipidemia
familial hypercholesterolemia · Hypercholesterolemia · Abnormal circulating lipid concentration
familial hypercholesterolemia · coronary artery disorder · familial hypercholesterolemia
cardiovascular disorder · familial hypercholesterolemia · diabetes mellitus
Hypercholesterolemia
familial hypercholesterolemia · coronary artery disorder · Hypercholesterolemia
cardiovascular disorder · Hypercholesterolemia
Tractability
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Research activity
Papers linked directly to this protein. This is the protein's own literature — descriptor-derived papers are kept separate below.
Most cited
Recent
Europe PMC papers linked directly to this protein.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
This ranking differs from Open Targets' own: re-weighting moves genetically-evidenced diseases above more heavily co-mentioned ones. The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through a drug that targets this protein, so each event is news about that drug rather than about the protein directly.
- Label change
Label change: EVOLOCUMAB (BLA125522)
- Label change
Label change: EVOLOCUMAB (BLA125522)
- Label change
Label change: EVOLOCUMAB (BLA125522)
- Label change
Label change: EVOLOCUMAB (BLA125522)
- New publicationLong-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease.
- Label change
Label change: EVOLOCUMAB (BLA125522)
- Indication expanded
Indication expansion: EVOLOCUMAB (BLA125522)
- Label change
Label change: EVOLOCUMAB (BLA125522)
- Regulatory approval
Approval: EVOLOCUMAB (BLA125522)
- New publicationEffects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.
- Supplemental approval
Supplemental approval: EVOLOCUMAB (BLA125522)
- New publicationImpact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects.
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.