What does PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) interact with?

PCSK9 Molecular Interactions

PCSK9 binds directly to the low-density lipoprotein receptor (LDLR) on hepatocyte surfaces, specifically targeting the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR, which leads to LDLR degradation and reduced LDL-cholesterol clearance from the bloodstream. 1, 2, 3

Primary Molecular Target: LDL Receptor

PCSK9's principal interaction is with the LDLR, where it functions as a secreted protein that promotes receptor degradation within the liver 4. The binding occurs through a specific structural interaction:

• The binding site on PCSK9 resides on the surface of its subtilisin-like catalytic domain, with key residues including Asp-374, Arg-194, and Phe-379 contributing to the interaction 3
• The LDLR EGF-A domain serves as the specific docking site for PCSK9 binding 5, 3
• This binding is distant from PCSK9's catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or prodomain of PCSK9 3

Mechanism of LDLR Degradation

The interaction between PCSK9 and LDLR follows a specific pathway:

• PCSK9 binds to LDLRs on the hepatocyte cell surface and promotes their degradation, reducing the number of receptors available to clear LDL from circulation 1, 2
• Secreted PCSK9 mediates LDLR degradation through receptor-mediated endocytosis, requiring both LDLR and the autosomal recessive hypercholesterolemia (ARH) gene product for efficient internalization 6
• Following endocytosis, PCSK9 displays endosomal-lysosomal intracellular localization, where LDLR degradation occurs 6

Secondary Interaction: LDL Particles

PCSK9 also interacts with LDL particles themselves in plasma:

• More than 40% of total plasma PCSK9 is associated with LDL particles in normolipidemic subjects 7
• PCSK9 binds to isolated LDL with a dissociation constant (K_D) of approximately 325 nM, and this binding is saturable 7
• The N-terminal region of the PCSK9 prodomain (amino acids 31-52) is required for binding to LDL in vitro 7
• LDL binding to PCSK9 inhibits PCSK9's ability to bind and degrade cell surface LDLRs, effectively blunting PCSK9-mediated LDLR degradation 7

Clinical Relevance of PCSK9-LDLR Interaction

Understanding this interaction has direct therapeutic implications:

• Individuals with PCSK9 loss-of-function mutations have increased numbers of LDL receptors on hepatocyte surfaces, promoting robust LDL-cholesterol clearance and lifelong cardiovascular protection 8
• Gain-of-function mutations that increase PCSK9 binding affinity to LDLR (such as D374Y or H306Y in the LDLR) result in enhanced LDLR degradation and hypercholesterolemia 5, 3
• PCSK9 inhibitor monoclonal antibodies (evolocumab, alirocumab) work by binding to PCSK9 and preventing its interaction with LDLR, thereby increasing LDLR availability and lowering LDL-cholesterol levels 1, 2

Complementary Interactions with Other Therapies

The PCSK9-LDLR interaction operates within a broader regulatory system:

• Statins increase LDLR expression through upregulation via the SREBP2 pathway, creating more targets for PCSK9 binding but also more receptors for LDL clearance 4, 9
• The modes of action of PCSK9 inhibitors, statins, and ezetimibe are complementary, with PCSK9 inhibition preventing LDLR degradation while statins increase LDLR expression 4