Cryo-EM structures of the human surfactant lipid transporter ABCA3

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 A. 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.

Automated summary

The ATP-binding cassette transporter ABCA3 plays a critical role in pulmonary surfactant synthesis. Mutations in human ABCA3 are the most common cause of inherited surfactant dysfunction disorders. This study presents the cryo-EM structures of human ABCA3 in two conformations and reveals a potential substrate binding mechanism and a conserved lateral access and extrusion mechanism for lipid transport mediated by ABCA transporters.