ABCA1, an ATP-binding cassette (ABC) subfamily A exporter, mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I (apoA-I) for generation of nascent high-density lipoprotein (HDL). Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency. Here, we report the cryo-EM structure of human ABCA1 with nominal resolutions of 4.1 Å for the overall structure and 3.9 Å for the massive extracellular domain. The nucleotide-binding domains (NBDs) display a nucleotide-free state, while the two transmembrane domains (TMDs) contact each other through a narrow interface in the intracellular leaflet of the membrane. In addition to TMDs and NBDs, two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allows potential interpretation of their diverse pathogenic mechanisms. Structural-based analysis suggests a plausible “lateral access” mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm.

中文翻译：

---

人血脂出口者ABCA1的结构

ATP结合盒（ABC）的一个亚家族ABCA1介导磷脂和胆固醇的细胞外排到细胞外受体载脂蛋白AI（apoA-I），以产生新生的高密度脂蛋白（HDL）。人ABCA1的突变与丹吉尔病和家族性HDL缺乏症有关。在这里，我们报告了人类ABCA1的冷冻电磁结构，其总体结构的标称分辨率为4.1Å，大规模胞外域的标称分辨率为3.9Å。核苷酸结合结构域（NBD）显示无核苷酸状态，而两个跨膜结构域（TMD）通过膜细胞内小叶中的狭窄界面相互接触。除了TMD和NBD以外，ABCA1的两个胞外域还包围着一个细长的疏水通道。数十种疾病相关突变的结构作图可以潜在地解释其多种致病机制。基于结构的分析表明，ABCA1介导的脂质输出可能存在“横向访问”机制，这可能与传统的交替访问范式不同。