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

PL Surdo, MJ Bottomley, A Calzetta, EC Settembre… - EMBO …, 2011 - embopress.org
PL Surdo, MJ Bottomley, A Calzetta, EC Settembre, A Cirillo, S Pandit, YG Ni, B Hubbard…
EMBO reports, 2011embopress.org
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 …
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.
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