BPS2026 – Structure of apolipoprotein B100 on low-density lipoprotein bound to receptor

Cardiovascular disease (CVD) has remained a leading cause of mortality for over three decades, accounting for about one-third of all global deaths. The underlying pathogenesis of CVD relates to the development of atherosclerosis, which begins with the deposition of low-density lipoproteins (LDL) into the wall of small arteries and the formation of lipid-rich plaques. Drug strategies for the prevention of the disease are largely centered on the interaction of low-density lipoprotein receptor (LDLR) with the apolipoprotein B-100 (apoB-100) protein on LDL. Mutations in apoB-100 or in LDLR cause familial hypercholesterolemia, an autosomal dominant disease characterized by a marked increase in LDL-cholesterol (LDL-C) and cardiovascular disease risk. Because the structure of apoB100 on LDL has not been determined, its interaction with LDLR is poorly understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of an apoB-100-nanobody complex and LDL bound to the LDLR, which can form a C 2 -symmetric, higher order complex. Using a local refinement approach, structures of the interfaces between apoB-100 and LDLR were determined. One binding interface is formed between several, small ligand binding modules of LDLR and a series of basic patches scattered (residues 3050–3600) along a beta-belt formed by apoB-100, encircling LDL. The other binding interface is formed between the b-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, key residues involved in LDL binding and dimer formation, corresponding to known mutations in either apoB100 or LDLR that are associated with elevated LDL-C, are described.