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.

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¹。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遗传疾病，其特征是 LDL 胆固醇 （LDL-C） 显着增加和心血管疾病风险增加²。apoB100 对 LDL 的结构及其与 LDLR 的相互作用知之甚少。在这里，我们展示了 apoB100 在与 LDLR 结合的 LDL 上的冷冻电子显微镜结构，以及可以形成 C₂ 对称的高阶复合物的纳米抗体复合物。使用局部细化，我们确定了 apoB100 和 LDLR 之间界面的高分辨率结构。一个结合界面在 LDLR 的几个小配体结合模块和一系列碱性贴片之间形成，这些片段分散在 apoB100 形成的β带上，环绕着 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。我们的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。此外，与高水平的 LDL-C 相关的 apoB100 或 LDLR 中已知的突变位于 LDL-LDLR 界面。