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Updated: Apr 23, 2026

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Sorting an LDL receptor with bound PCSK9 to intracellular degradation
1Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Objective:
This article reviews the mechanism by which the low density lipoprotein receptor (LDLR) that has bound proprotein convertase subtilisin/kexin type 9 (PCSK9), is rerouted to intracellular degradation instead of being recycled.
Methods:
A search of relevant published literature has been conducted.
Results:
PCSK9 binds to the LDLR at the cell surface. It is the catalytic domain of PCSK9 that binds to the epidermal growth factor repeat A of the LDLR. The LDLR:PCSK9 complex is internalized through clathrin-mediated endocytosis. Due to an additional electrostatic interaction at acidic pH between the C-terminal domain of PCSK9 and the ligand-binding domain of the LDLR, PCSK9 remains bound to the LDLR in the sorting endosome. As a consequence, the LDLR fails to adopt a closed conformation and is degraded instead of being recycled. The mechanism for the failure of the LDLR to recycle appears to involve ectodomain cleavage of the extended LDLR by a cysteine cathepsin in the sorting endosome. The cleaved LDLR ectodomain will be confined to the vesicular part of the sorting endosome for degradation in the endosomal/lysosomal tract.
Conclusion:
Ectodomain cleavage of an LDLR with bound PCSK9 in the sorting endosome disrupts the normal recycling of the LDLR.
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