A 35-year-old man with familial hypercholesterolemia undergoes genetic testing. The mutation is identified in the PCSK9 gene causing a gain-of-function variant. PCSK9 promotes LDL receptor degradation by binding the receptor after LDL dissociation. A new monoclonal antibody (evolocumab) neutralizes circulating PCSK9. By which mechanism does PCSK9 normally prevent LDL receptor recycling?

• A PCSK9 phosphorylates the cytoplasmic tail of the LDL receptor, redirecting it to the lysosome
• B PCSK9 inhibits HMG-CoA reductase in the endoplasmic reticulum, reducing LDL receptor synthesis
• C PCSK9 cleaves the extracellular domain of the LDL receptor, releasing it from the hepatocyte surface
• D PCSK9 binds the LDL receptor in the endosome, preventing receptor conformational change needed for LDL release ✓

Explanation

PCSK9 (proprotein convertase subtilisin/kexin type 9) is secreted by hepatocytes and binds the extracellular EGF-A domain of the LDL receptor. After LDL-LDL receptor-PCSK9 complex is internalized in endosomes, the lower pH of the endosome would normally cause the receptor to release LDL and recycle to the cell surface. However, PCSK9 binding stabilizes the closed (inactive) conformation of the LDL receptor in the acidic endosome, preventing the conformational change required for LDL release. The entire complex is then routed to lysosomes for degradation instead of receptor recycling. Gain-of-function PCSK9 mutations or high PCSK9 levels therefore reduce surface LDL receptor density, elevating LDL cholesterol.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.