Structure of the Human Lipid Exporter ABCA1
Structure of the Human Lipid Exporter ABCA1
复制标题
DOI：
10.1016/j.cell.2017.05.020
复制
发表时间：
2017-06-15
期刊：
影响因子：
64.5
通讯作者：
Gong, Xin
中科院分区：
文献类型：
--
作者：
Qian, Hongwu;Zhao, Xin;Gong, Xin
ABCA 1是一种ATP结合盒（ABC）亚家族A输出蛋白，介导磷脂和胆固醇向细胞外受体载脂蛋白A-I（apoA-I）的流出，生成新生高密度脂蛋白（HDL）。人类ABCA 1突变与丹吉尔病和家族性HDL缺乏症相关。在这里，我们报告了人类ABCA 1的冷冻-EM结构，其总体结构的标称分辨率为4.1埃，大规模细胞外结构域的标称分辨率为3.9埃。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）通过膜的细胞内小叶中的狭窄界面彼此接触。除了TMD和NBD之外，ABCA 1的两个细胞外结构域包围细长的疏水通道。数十种疾病相关突变的结构图谱可以解释其不同的致病机制。基于结构的分析表明，ABCA 1介导的脂质输出可能是一个合理的“横向访问”机制，可能不同于传统的交替访问范式。
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 angstrom for the overall structure and 3.9 angstrom 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.