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

Mart Reimund, Altaira D. Dearborn (altaira.dearborn@nih.gov), Giorgio Graziano, Haotian Lei, Anthony M. Ciancone, Ashish Kumar, Ronald Holewinski, Edward B. Neufeld, Francis J. O’Reilly, Alan T. Remaley (alan.remaley@nih.gov) and Joseph Marcotrigiano (joseph.marcotrigiano@nih.gov)
Additional contact information
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
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08223-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:638:y:2025:i:8051:d:10.1038_s41586-024-08223-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08223-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla (sonal.shukla@springer.com) and Springer Nature Abstracting and Indexing (indexing@springernature.com).