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Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.

By Lo Surdo, Paola; Bottomley, Matthew J.; Calzetta, Alessandra; Settembre, Ethan C.; Cirillo, Agostino; Pandit, Shilpa; Ni, Yan G.; Hubbard, Brian; Sitlani, Ayesha; Carfi, Andrea
From EMBO Reports (2011), 12(12), 1300-1305. Language: English, Database: CAPLUS, DOI:10.1038/embor.2011.205

The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-d. lipoprotein receptor (LDLR) levels and cardiovascular health. We have detd. the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and β-propeller domains, resp. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.

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