Reactome | PCSK9 binds LDLR

PCSK9 binds LDLR

Stable Identifier

R-HSA-6784734

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds to LDLR (Low-density lipoprotein receptor) on the cell surface. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR (Zhang et al. 2007). The complex PCSK9:LDLR is internalized via clathrin-mediated endocytosis and then routed to lysosomes via a mechanism that does not require ubiquitination and is distinct from the autophagy and proteosomal degradation pathways. In lysosomes, the affinity of the interaction between PCSK9 and LDLR dramatically increases. This promotes the final degradation of PCSK9 and LDLR without recycling. Monoclonal antibodies targeting PCSK9 have been shown to markedly reduce LDL cholesterol levels and are a novel treatment strategy for adults with hypercholesterolemia (Navarese et al. 2015).

Literature References

PubMed ID	Title	Journal	Year
25915661	Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis Navarese, EP, Kolodziejczak, M, Schulze, V, Gurbel, PA, Tantry, U, Lin, Y, Brockmeyer, M, Kandzari, DE, Kubica, JM, D'Agostino, RB, Kubica, J, Volpe, M, Agewall, S, Kereiakes, DJ, Kelm, M	Ann. Intern. Med.	2015
17452316	Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation Zhang, DW, Lagace, TA, Garuti, R, Zhao, Z, McDonald, M, Horton, JD, Cohen, JC, Hobbs, HH	J. Biol. Chem.	2007