Cryo-EM structures of human ABCA7 provide insights into its phospholipid translocation mechanisms

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 in a nucleotide-bound, closed state at resolutions between 3.6 and 4.0 angstrom. 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.

Automated summary

Phospholipid extrusion by ABC subfamily A (ABCA) exporters is essential for cellular physiology, but the molecular details of substrate interactions and transport mechanisms are still not well understood. In this study, cryo-EM structures of lipid-embedded human ABCA7 in different states were determined, revealing the structural framework for substrate entry and exit from ABCA7 and providing insights into the underlying conformational transitions. Combining functional analysis and molecular dynamics simulations, the study also shed light on lipid partitioning and localized membrane perturbations that contribute to ABCA7 function and may have implications for other ABCA family transporters.