Phospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of the underlying substrate interactions and transport mechanisms remain poorly resolved at the molecular level. Here we report cryo-EM structures of lipid-embedded human ABCA7 in an open state and a nucleotide-bound, closed state at resolutions between 3.6-4.0 Å. The former reveals an ordered patch of bilayer lipids traversing the transmembrane domain (TMD), while the latter reveals a lipid-free, closed TMD with a small extracellular opening. These structures offer a structural framework for both substrate entry and exit from the ABCA7 TMD and highlight conserved rigid-body motions that underlie the associated conformational transitions. Combined with functional analysis and molecular dynamics (MD) simulations, our data also shed light on lipid partitioning into the ABCA7 TMD and localized membrane perturbations that underlie ABCA7 function and have broader implications for other ABCA family transporters.

中文翻译：

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捕捉人 ABCA7 中膜脂和结构转变的相互作用

ABC 亚科 A (ABCA) 出口商的磷脂挤出是细胞生理学的核心，尽管底层底物相互作用和转运机制的细节在分子水平上仍然很难解决。在这里，我们报告了脂质嵌入的人类 ABCA7 在开放状态和核苷酸结合、封闭状态下的冷冻电镜结构，分辨率在 3.6-4.0 Å 之间。前者揭示了穿过跨膜结构域 (TMD) 的有序双层脂质斑块，而后者揭示了具有小细胞外开口的无脂质、封闭的 TMD。这些结构为底物进入和退出 ABCA7 TMD 提供了一个结构框架，并突出了作为相关构象转变基础的保守刚体运动。结合功能分析和分子动力学（MD）模拟，