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

Mart Reimund, Altaira D. Dearborn (), Giorgio Graziano, Haotian Lei, Anthony M. Ciancone, Ashish Kumar, Ronald Holewinski, Edward B. Neufeld, Francis J. O’Reilly, Alan T. Remaley () and Joseph Marcotrigiano ()
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Mart Reimund: National Institutes of Health
Altaira D. Dearborn: National Institutes of Health
Giorgio Graziano: National Institutes of Health
Haotian Lei: National Institutes of Health
Anthony M. Ciancone: National Institutes of Health
Ashish Kumar: National Institutes of Health
Ronald Holewinski: Leidos Biomedical Research
Edward B. Neufeld: National Institutes of Health
Francis J. O’Reilly: National Institutes of Health
Alan T. Remaley: National Institutes of Health
Joseph Marcotrigiano: National Institutes of Health

Nature, 2025, vol. 638, issue 8051, 829-835

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08223-0

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