Cited by 31Drug Transport and Resistance MechanismsLipid Membrane Structure and BehaviorProtein Structure and Dynamics

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

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Le, Le Thi My, Thompson, James Robert, Dehghani‐Ghahnaviyeh, Sepehr, Pant, Shashank, Dang, Phuoc Xuan, French, Jarrod Bradley, Kanikeyo, Takahisa, Tajkhorshid, Emad +1 more·2023·The EMBO Journal

Published version of a preprint

Abstract

Abstract 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 a nucleotide-bound, closed state at resolutions between 3.6-4.0 Å. 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.

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Authors
Le, L. T. M., Thompson, J. R., Dehghani‐Ghahnaviyeh, S., Pant, S., Dang, P. X., French, J. B., Kanikeyo, T., Tajkhorshid, E., & Alam, A.
Affiliations
  • University of Minnesota (US)
  • University of Illinois Urbana-Champaign (US)
  • Mayo Clinic (US)
Corresponding author
Alam, Amer
Venue
The EMBO Journal
Published
2022-12-09
Volume
42
Issue
3
Pages
e111065-e111065
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
OpenAlex
W4310960009
Cited by
31
References
66
Citations by year
2026: 4 · 2025: 8 · 2024: 9 · 2023: 4 · 2022: 3 · 2021: 3
FWCI
2.51
Type
journal article
Language
en
Open access
Locations
  • The EMBO Journal (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • eXtreme Science and Engineering Discovery Environment (MCA06N060)
  • HHS ¦ NIH ¦ National Institute of General Medical Sciences (P41‐GM104601, R01‐GM123455, R35GM124898)
  • HHS ¦ NIH ¦ National Institute on Aging (1R21‐AG069180‐01A1)
  • Hormel Foundation
  • Cure Alzheimer's fund
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
ABCA7, phospholipid translocation, transmembrane domain, lipid partitioning, membrane perturbation
MeSH terms
Biological Transport, Humans, Phospholipids, ATP-Binding Cassette Transporters, Cryoelectron Microscopy, Interferon Regulatory Factors, Molecular Dynamics Simulation

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