美国密苏里大学Zachary T. Berndsen和C. Keith Cassidy合作解析了人类低密度脂蛋白中载脂蛋白B100的结构。该研究于2024年12月11日在线发表于国际一流学术期刊《自然》。

研究人员表示，低密度脂蛋白（LDL）在脂质和胆固醇代谢中发挥着核心作用，并且是动脉粥样硬化发展的关键因素。动脉粥样硬化是全球死亡的主要原因之一。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。但由于其尺寸和复杂的脂质关联，一直是结构研究的重大挑战。

通过采用冷冻电镜、AlphaFold2和基于分子动力学的精细化整合方法，研究人员首次展示了apoB100的结构，在大部分区域达到了亚纳米分辨率。该结构由一个大的球形N端结构域和一个约61纳米长的连续两性β-sheet组成，后者像皮带一样环绕在LDL颗粒周围。在“β皮带”两侧几乎对称分布着9个策略性定位的跨链插入物，这些插入物跨越脂质表面，通过长程相互作用的网络提供额外的结构支持。

研究人员进一步将该结构与超过200个分子内交联的综合列表进行比较，发现两者之间高度一致。这些结果揭示了apoB100的各个结构域如何协同作用，以维持LDL的形状和凝聚力，适应不同颗粒大小。更广泛地说，这些发现推进了人们对LDL合成、形态和功能的基础理解，并将有助于加速潜在新疗法的设计。

附：英文原文

Title: The structure of apolipoprotein B100 from human low-density lipoprotein

Author: Berndsen, Zachary T., Cassidy, C. Keith

Issue&Volume: 2024-12-11

Abstract: 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.

DOI: 10.1038/s41586-024-08467-w

Source: https://www.nature.com/articles/s41586-024-08467-w