Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure
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ABCA1, ABCG1 transporters, and SR-B1 receptor are the major proteins involved in cholesterol efflux from cells. We superposed in silico the location of putative cholesterol (Chol)-binding motifs CRAC/CARC and CCM in human ABCA1, ABCG1, and SR-B1 with (1) transmembrane protein topology, (2) a profile of structural order of protein, and (3) with an influence of single amino acid substitutions on protein structure and function. ABCA1, ABCG1, and SR-B1 molecules contain 50, 19, and 13 Chol-binding motifs, respectively, that are localized either in membrane helices, or at membrane–water interface, or in water-exposed protein regions. Arginine residues in motifs that coincide with molecular recognition features within intrinsically disordered regions of the transporters are suggested to be important in cholesterol binding; cholesterol–arginine interaction may result in the induction of local order in protein structure. Chol-binding motifs in membrane helices may immobilize cholesterol, while motifs at membrane–water interface may be involved into the efflux of “active” cholesterol. Cholesterol may interfere with ATP binding in both nucleotide-binding domains of ABCA1 structure. For ABCA1 and ABCG1, but not for SR-B1, the presence of mirror code as a CARC–CRAC vector couple in the C-terminal helices controlling protein–cholesterol interactions in the outer and inner membrane leaflets was evidenced. We propose the role of Chol-binding motifs with different immersion in membrane in transport of different cholesterol pools by ABCA1 and ABCG1.
KeywordsABCA1 ABCG1 SR-B1 ApoA-I Cholesterol-binding domains
Cholesterol consensus motif
Cholesterol recognition/interaction amino acid consensus
Human gene mutation database
Molecular recognition feature
This study was funded by the grants 16-04-00067 and 17-04-00217 from the Russian Fund for Basic Research.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research Involving Human and Animal Participants
This article does not contain any studies with human participants or animals performed by any of the authors.
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