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Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure

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Abstract

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.

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Abbreviations

apoA-I:

Apolipoprotein A-I

CARC:

Inverted CRAC

CCM:

Cholesterol consensus motif

Chol:

Cholesterol

CRAC:

Cholesterol recognition/interaction amino acid consensus

HDL:

High-density lipoproteins

HDL-C:

HDL cholesterol

HGMD:

Human gene mutation database

MoRF:

Molecular recognition feature

NBD:

Nucleotide-binding domain

SNP:

Single-nucleotide polymorphism

TM:

Transmembrane

TMD:

Transmembrane domain

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Funding

This study was funded by the grants 16-04-00067 and 17-04-00217 from the Russian Fund for Basic Research.

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Authors and Affiliations

  1. National Research Centre for Preventive Medicine, 10, Petroverigsky Street, Moscow, Russia, 101990

    Alexander D. Dergunov, Eugeny V. Savushkin & Dmitry Y. Litvinov

  2. Institute of Molecular Genetics of the Russian Academy of Sciences, 2 Kurchatov Square, Moscow, Russia, 123182

    Liudmila V. Dergunova

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  1. Alexander D. Dergunov
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  2. Eugeny V. Savushkin
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  3. Liudmila V. Dergunova
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  4. Dmitry Y. Litvinov
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Correspondence to Alexander D. Dergunov.

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Dergunov, A.D., Savushkin, E.V., Dergunova, L.V. et al. Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure. J Membrane Biol 252, 41–60 (2019). https://doi.org/10.1007/s00232-018-0056-5

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