Molecular basis for LDL receptor recognition by PCSK9
Molecular basis for LDL receptor recognition by PCSK9
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DOI：
10.1073/pnas.0712064105
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发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Deisenhofer, Johann
中科院分区：
文献类型：
--
作者：
Kwon, Hyock Joo;Lagace, Thomas A.;Deisenhofer, Johann
枯草杆菌蛋白原转换酶9(PCSK9)通过与肝细胞表面的低密度脂蛋白受体(LDLRs)结合，调节翻译后的LDLRs，导致其降解。PCSK9的结合位点定位于LDLR的表皮生长因子样重复A(EGF-A)结构域。在这里，我们描述了PCSK9和LDLR的EGF-A结构域之间的复合物的晶体结构。低密度脂蛋白受体EGF-A结构域的结合位点位于含有天冬氨酸-374的PCSK9‘S枯草杆菌素样催化结构域的表面，该残基的功能获得突变(Asp-374-Tyr)增加了PCSK9与低密度脂蛋白受体的亲和力，并增加了人体血浆低密度脂蛋白-胆固醇(L DL-C)水平。PCSK9上的结合表面远离其催化部位，EGF-A结构域不与C末端结构域或原结构域接触。PCSK9上的点突变改变了导致EGF-A结合的关键残基(Arg-194和Phe-379)，大大减少了与LDLR胞外域的结合。PCSK9与低密度脂蛋白受体EGF-A结构域的复合体结构决定了阻断药物的潜在治疗靶点，这些药物可以干扰体内这种相互作用，从而增加低密度脂蛋白受体的功能，降低血浆低密度脂蛋白-C水平。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRS) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels.