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Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH
Author(s) -
Surdo Paola Lo,
Bottomley Matthew J,
Calzetta Alessandra,
Settembre Ethan C,
Cirillo Agostino,
Pandit Shilpa,
Ni Yan G,
Hubbard Brian,
Sitlani Ayesha,
Carfí Andrea
Publication year - 2011
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2011.205
Subject(s) - pcsk9 , ldl receptor , chemistry , kexin , degradation (telecommunications) , receptor , biochemistry , microbiology and biotechnology , biophysics , cholesterol , biology , lipoprotein , computer science , telecommunications
The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low‐density lipoprotein receptor (LDLR) levels and cardiovascular health. We have determined 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, respectively. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.