Low-density lipoprotein (LDL) plays a central role in lipid and cholesterol metabolism and is a key agent in the development and progression of atherosclerosis, the leading cause of mortality worldwide1,2. Apolipoprotein B100 (apoB100), one of the largest proteins in the genome, is the primary structural and functional component of LDL, yet its size and complex lipid associations have posed major challenges for structural studies3. Here we present the first structure of apoB100 resolved to sub-nanometer resolution in most regions using an integrative approach of cryo-electron microscopy, AlphaFold24, and molecular dynamics-based refinement5. The structure consists of a large globular N-terminal domain and a ~61 nm long continuous amphipathic β-sheet that wraps around the LDL particle like a belt. Distributed quasi-symmetrically across the two sides of the “β-belt” are 9 strategically located inter-strand inserts that extend across the lipid surface to provide additional structural support through a network of long-range interactions. We further compare our structure to a comprehensive list of >200 intramolecular crosslinks and find close agreement between the two. These results suggest a mechanism for how the various domains of apoB100 act in concert to maintain LDL shape and cohesion across a range of particle sizes. More generally, they advance our fundamental understanding of LDL synthesis, form and function and will help accelerate the design of potential new therapeutics.
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Supplementary Discussion, Supplementary Methods, Supplementary References, Supplementary Figs 1–7, Supplementary Tables 1–8 and descriptions for Supplementary Videos 1–3 – see Contents for details.
Data showcase. Video showing the cryo-EM reconstruction of human LDL at several different contour levels without and with the MDFF refined full-length atomic model of apoB100. Also shown is the focused refinement of the apoB100 N-terminal domain with the docked atomic model. Video was prepared using ChimeraX and Blender (Version 4.2.3 (4.2.3 2024-10-15)).
MDFF refinement of the NTD and β-belt structure. Video showing sequential MDFF refinement of the apoB100 NTD and β-belt domains into the high-contour cryo-EM map. Video was prepared using VMD.
Cryo-EM 3-D classification volume morph. Video showing a morph between multiple cryo-EM 3-D classes generated using CryoSparc 3-D variability analysis meant to highlight the structure flexibility of apoB100 on the surface of slightly different sized and shaped LDL particles. The cryo-EM map was coloured by the fit refined atomic model of apoB100. Video was prepared in ChimeraX and and Blender (Version 4.2.3 (4.2.3 2024-10-15)).