Biochemistry · Enzyme
PCSK9 !
PCSK9 binds the LDL receptor and sends it to be destroyed; blocking it leaves more receptors and lowers LDL cholesterol sharply.
Updated 2026-11-01
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Key facts
- A liver serine protease that cleaves itself once; afterwards it acts as a binding protein, not as an enzyme.
- It binds the LDL receptor EGF-A domain; the complex is internalised and the receptor is degraded in the lysosome instead of recycling.
- Gain-of-function variants cause familial hypercholesterolaemia; loss-of-function variants give low LDL and fewer heart attacks.
- SREBP-2 induces it together with the LDL receptor, so statins raise PCSK9.
- Also called
- Proprotein convertase subtilisin/kexin type 9
- EC number
- 3.4.21.-
- Genes
- PCSK9
- Structure (PDB)
- 3BPS
Structure
- Prodomain, subtilisin-like catalytic domain and a cysteine/histidine-rich C-terminal domain; the prodomain stays bound and blocks the active site.
- Structure 3BPS shows PCSK9 bound to the LDL receptor EGF-A domain.
Regulation
- SREBP-2 raises its transcription (statins raise it too).
- It circulates in plasma and acts on receptors on the hepatocyte surface.
Inhibitors and toxins
- Monoclonal antibodies (evolocumab, alirocumab)
- Small interfering RNA (inclisiran), which lowers its production in the liver
Clinical notes
- PCSK9 inhibitors lower LDL by about 50–60% on top of a statin and reduce cardiovascular events.
- They are used in familial hypercholesterolaemia and very high risk when a statin is not enough.
- It was discovered in families with familial hypercholesterolaemia lacking LDLR or APOB variants.
Drugs that act here
Related conditions
Related
Test yourself
Think of the answer, then tap the question to see it.
How does PCSK9 raise LDL cholesterol?
It sends the LDL receptor to lysosomal degradation: fewer receptors clear less LDL.
Why do statins raise circulating PCSK9?
They activate SREBP-2, which induces both the LDL receptor and PCSK9.
What do loss-of-function PCSK9 variants do?
Lifelong low LDL and less coronary disease.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: PCSK9: Proprotein convertase subtilisin/kexin type 9 (human) (UniProt, 2026); PCSK9 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 3BPS: PCSK9:EGF-A complex (RCSB Protein Data Bank, 2026); Cholesterol Medicines: MedlinePlus (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.