Structure of the Human Lipid Exporter ABCA1.

TitleStructure of the Human Lipid Exporter ABCA1.
Publication TypeJournal Article
Year of Publication2017
AuthorsQian, H, Zhao, X, Cao, P, Lei, J, Yan, N, Gong, X
JournalCell
Volume169
Issue7
Pagination1228-1239.e10
Date Published2017 Jun 15
ISSN1097-4172
KeywordsAmino Acid Sequence, ATP Binding Cassette Transporter 1, Cryoelectron Microscopy, Humans, Models, Molecular, Protein Domains, Sequence Alignment
Abstract

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 Å for the overall structure and 3.9 Å 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.

DOI10.1016/j.cell.2017.05.020
Alternate JournalCell
PubMed ID28602350