美国国立卫生研究院Joseph Marcotrigiano，Alan T. Remaley和Altaira D. Dearborn共同合作，近期取得重要工作进展。他们研究解析了载脂蛋白B100与低密度脂蛋白受体结合的结构。相关研究成果2024年12月11日在线发表于《自然》杂志上。

据介绍，载脂蛋白B100（apoB100）是低密度脂蛋白（LDL）的结构成分，也是LDL受体（LDLR）的配体。apoB100或LDLR突变会导致家族性高胆固醇血症，这是一种常染色体显性疾病，其特征是LDL胆固醇（LDL-C）显著增加，心血管疾病风险更高。LDL上apoB100的结构及其与LDLR的相互作用知之甚少。

研究人员报道了LDL上apoB100的冷冻镜结构，该结构与LDLR和纳米体复合物结合，可以形成C2对称的高阶复合物。通过局部细化，研究人员确定了apoB100和LDLR之间界面的高分辨率结构。LDLR的几个小配体结合模块和一系列基本斑块之间形成了一个结合界面，这些斑块沿着apoB100形成的β带散布，环绕LDL。另一个结合界面形成于LDLR的β-螺旋桨结构域和apoB100的N端结构域之间。

总之，这一研究结果揭示了这两个界面如何参与LDL二聚体的形成，以及LDLR如何在LDL和自结合构象之间循环。与高水平LDL-C相关的apoB100或LDLR中的已知突变位于LDL-LDLR界面。

附：英文原文

Title: Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor

Author: Reimund, Mart, Dearborn, Altaira D., Graziano, Giorgio, Lei, Haotian, Ciancone, Anthony M., Kumar, Ashish, Holewinski, Ronald, Neufeld, Edward B., OReilly, Francis J., Remaley, Alan T., Marcotrigiano, Joseph

Issue&Volume: 2024-12-11

Abstract: Apolipoprotein B100 (apoB100) is a structural component of low-density lipoprotein (LDL) and a ligand for the LDL receptor (LDLR)1. Mutations in apoB100 or in LDLR cause familial hypercholesterolaemia, an autosomal dominant disease that is characterized by a marked increase in LDL cholesterol (LDL-C) and a higher risk of cardiovascular disease2. The structure of apoB100 on LDL and its interaction with LDLR are poorly understood. Here we present the cryo-electron microscopy structures of apoB100 on LDL bound to the LDLR and a nanobody complex, which can form a C2-symmetric, higher-order complex. Using local refinement, we determined high-resolution structures of the interfaces between apoB100 and LDLR. One binding interface is formed between several small-ligand-binding modules of LDLR and a series of basic patches that are scattered along a β-belt formed by apoB100, encircling LDL. The other binding interface is formed between the β-propeller domain of LDLR and the N-terminal domain of apoB100. Our results reveal how both interfaces are involved in LDL dimer formation, and how LDLR cycles between LDL- and self-bound conformations. In addition, known mutations in either apoB100 or LDLR, associated with high levels of LDL-C, are located at the LDL–LDLR interface.

DOI: 10.1038/s41586-024-08223-0

Source: https://www.nature.com/articles/s41586-024-08223-0