Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor
成果类型：
Article
署名作者：
Reimund, Mart; Dearborn, Altaira D.; Graziano, Giorgio; Lei, Haotian; Ciancone, Anthony M.; Kumar, Ashish; Holewinski, Ronald; Neufeld, Edward B.; O'Reilly, Francis J.; Remaley, Alan T.; Marcotrigiano, Joseph
署名单位：
National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research
刊物名称：
Nature
ISSN/ISSBN：
0028-2213
DOI：
10.1038/s41586-024-08223-0
发表日期：
2025-02-20
关键词：
摘要：
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 beta-belt formed by apoB100, encircling LDL. The other binding interface is formed between the beta-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.