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; Joseph Marcotrigiano

doi:10.1038/s41586-024-08223-0

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

Nature. 2024 Dec 11. doi: 10.1038/s41586-024-08223-0. Online ahead of print.

Authors

Affiliations

¹ Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
² Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
³ Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁴ Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
⁵ Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁶ Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA.
⁷ Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
⁸ Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].

^# Contributed equally.

PMID: 39663455
DOI: 10.1038/s41586-024-08223-0

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.