ATP结合盒运输机
生物发生
三磷酸腺苷
跨膜蛋白
生物物理学
细胞生物学
运输机
化学
脂质双层
低温电子显微
结合位点
生物化学
生物
膜
基因
受体
作者
Tian Xie,Zi-Ke Zhang,Jian Yue,Qi Fang,Xin Gong
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-04-08
卷期号:8 (14)
被引量:10
标识
DOI:10.1126/sciadv.abn3727
摘要
The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter ABCA3 plays a critical role in pulmonary surfactant biogenesis. Mutations in human ABCA3 have been recognized as the most frequent causes of inherited surfactant dysfunction disorders. Despite two decades of research, in vitro biochemical and structural studies of ABCA3 are still lacking. Here, we report the cryo-EM structures of human ABCA3 in two distinct conformations, both at resolution of 3.3 Å. In the absence of ATP, ABCA3 adopts a "lateral-opening" conformation with the lateral surfaces of transmembrane domains (TMDs) exposed to the membrane and features two positively charged cavities within the TMDs as potential substrate binding sites. ATP binding induces pronounced conformational changes, resulting in the collapse of the potential substrate binding cavities. Our results help to rationalize the disease-causing mutations in human ABCA3 and suggest a conserved "lateral access and extrusion" mechanism for both lipid export and import mediated by ABCA transporters.
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