The regulatory domains of the lipid exporter ABCA1 form domain swapped latches.

Autor: Aller SG; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, United States of America., Segrest JP; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2022 Feb 04; Vol. 17 (2), pp. e0262746. Date of Electronic Publication: 2022 Feb 04 (Print Publication: 2022).
DOI: 10.1371/journal.pone.0262746
Abstrakt: ABCA1 and ABCA4 are enigmatic because they transport substrates in opposite directions yet share >50% amino acid identity. ABCA4 imports lipid conjugates but ABCA1 exports lipids. Both hydrolyze ATP to drive transport, and both contain cytoplasmic regulatory domains (RDs) following nucleotide-binding domains (NBDs) in the primary structure. The tertiary structures of several ABC importers, including ABCA4, show that each RD forms a domain-swapped latch that locks onto the opposing RD and holds the NBDs close together. Crucially, sequences encoding the RDs and their bridges are among the most conserved in the entire ABC-A subfamily. In the original cryo-EM structure of ABCA1, the RDs were modeled without crossover. After close inspection of that cryo-EM density map and the recent structure of ABCA4, we propose that the RDs of ABCA1 also form a domain-swapped latch. A refined ABCA1 model containing latches exhibited significantly improved overall protein geometry. Critically, the conserved crossover sequence leading to the RD-domain swap is directly supported by the original cryo-EM density map of ABCA1 and appears to have been overlooked. Our refined ABCA1 model suggests the possibility that ABCA1, despite being an exporter, has highly restrained NBDs that suggest a transport mechanism that is distinct from 'alternating access'.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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