Journal Article

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

Graziano, Giorgio, Ciancone, Anthony M., Neufeld, Edward B., Remaley, Alan T., Marcotrigiano, Joseph, O’Reilly, Francis J., Reimund, Mart, Dearborn, Altaira D., Lei, Haotian, Kumar, Ashish, Holewinski, Ronald

2025

Overview

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 disease 2 . 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 C 2 -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. Cryo-electron microscopy structures of apolipoprotein B100 (apoB100) in complex with the LDL receptor (LDLR) provide insight into binding interfaces and explain how mutations in apoB100 or in LDLR can give rise to familial hypercholesterolaemia.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/443/592/75 / 631/535/1258/1259 / Apolipoprotein B-100 - chemistry / Apolipoprotein B-100 - genetics / Apolipoprotein B-100 - metabolism / Apolipoprotein B-100 - ultrastructure / Apolipoproteins / Binding / Binding Sites / Cardiovascular disease / Cardiovascular diseases / Cholesterol / Cryoelectron Microscopy / Density / Electron microscopy / Epidermal growth factor / Health risks / Humanities and Social Sciences / Humans / Hypercholesterolemia / Interfaces / Ligands / Lipids / Lipoproteins / Lipoproteins, LDL - chemistry / Lipoproteins, LDL - metabolism / Lipoproteins, LDL - ultrastructure / Low density lipoprotein / Low density lipoprotein receptors / Microscopy / Models, Molecular / multidisciplinary / Mutation / Nanobodies / Pathogenesis / Protein Binding / Protein Domains / Receptor density / Receptors / Receptors, LDL - chemistry / Receptors, LDL - genetics / Receptors, LDL - metabolism / Receptors, LDL - ultrastructure / Science / Science (multidisciplinary) / Single-Domain Antibodies - chemistry / Single-Domain Antibodies - metabolism / Single-Domain Antibodies - ultrastructure