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 worldwide^1,2. 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.

低密度脂蛋白 （LDL） 在脂质和胆固醇代谢中起着核心作用，是动脉粥样硬化发展和进展的关键因素，动脉粥样硬化是全球死亡的主要原因^1,2。载脂蛋白 B100 （apoB100） 是基因组中最大的蛋白质之一，是 LDL 的主要结构和功能成分，但其大小和复杂的脂质结合对结构研究构成了重大挑战³。在这里，我们介绍了 apoB100 的第一个结构，它使用冷冻电子显微镜、AlphaFold2⁴ 和基于分子动力学的精修⁵ 的综合方法在大多数区域解析到亚纳米分辨率。该结构由一个大的球状 N 末端结构域和一个 ~61 nm 长的连续两亲性 β 片组成，该片像带一样包裹着 LDL 颗粒。准对称分布在“β带”两侧的是 9 个战略性定位的链间插入物，它们延伸到脂质表面，通过长距离相互作用网络提供额外的结构支持。我们进一步将我们的结构与 >200 分子内交联的完整列表进行比较，并发现两者之间非常一致。这些结果表明了 apoB100 的各个结构域如何协同作用以在一系列粒径范围内保持 LDL 形状和内聚力的机制。更广泛地说，它们促进了我们对 LDL 合成、形式和功能的基本理解，并将有助于加速潜在新疗法的设计。