Cholesterol consensus domain
Cholesterol Consensus Domains are highly conserved protein motifs that bind cholesterol. They are commonly located in alpha helices of transmembrane domains within integral membrane proteins.[1]
Description
[edit]CRAC (cholesterol-recognition amino acid consensus) is defined by the amino acid sequence (L/V)-X1–5-(Y)-X1–5-(K/R) where X1-5 represents 5 ambiguous amino acids.[2] The CRAC motif on a transmembrane protein is preferentially located in the inner leaflet.[3] CARC is the reverse sequence of the CRAC motif, characterized by (K/R)-X1–5-(Y/F)-X1–5-(L/V), and is mostly found on the outer leaflet portion of a transmembrane protein. Tyrosine is a mandatory central residue in CRAC, while CARC can bind using either a central tyrosine or phenylalanine to support pi bond stacking. The basic lysine and arginine residues at the C-terminus of CRAC and at the N-terminus of CARC ensure positioning of cholesterol's apex hydrophilic hydroxyl group at the periphery of the membrane such that the hydrophobic majority of cholesterol is submerged in the membrane.[3]
Cholesterol consensus domains have been studied in several protein classes including receptors (benzodiazepine receptors, nicotinic acetylcholine receptors, GPCRs) and transporters (ATP-binding cassette (ABC) transporters ABCG1, P-glycoprotein (P-gp), and solute carrier transporters like human organic cation transporter 2).[citation needed]
Cholesterol binding is associated with increased activity of ion-channel proteins. Cholesterol binding may be competitively inhibitory to ATPase activity and substrate export of transporter P-gp in multi-drug-resistant (MDR) cells, resulting in a slowed export rate of anti-cancer molecules from the cell.[4] However, P-gp basal ATPase activity was inhibited after cholesterol depletion by Methyl-beta-cyclodextrin, suggesting that cholesterol binding activates P-gp ATPase activity.[4]
References
[edit]- ^ Fantini, Jacques; Barrantes, Francisco J. (2013-02-28). "How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains". Frontiers in Physiology. 4: 31. doi:10.3389/fphys.2013.00031. ISSN 1664-042X. PMC 3584320. PMID 23450735.
- ^ Di Scala, Coralie; Baier, Carlos J.; Evans, Luke S.; Williamson, Philip T. F.; Fantini, Jacques; Barrantes, Francisco J. (2017-01-01), Levitan, Irena (ed.), "Chapter One - Relevance of CARC and CRAC Cholesterol-Recognition Motifs in the Nicotinic Acetylcholine Receptor and Other Membrane-Bound Receptors", Current Topics in Membranes, Sterol Regulation of Ion Channels, 80, Academic Press: 3–23, doi:10.1016/bs.ctm.2017.05.001, PMID 28863821, retrieved 2025-02-15
- ^ a b Barrantes, Francisco J. (2016-12-22). "Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale". Biomedical Spectroscopy and Imaging. 5 (s1): S67 – S86. doi:10.3233/BSI-160158.
- ^ a b Garrigues, Alexia; Escargueil, Alexandre E.; Orlowski, Stéphane (2002-08-06). "The multidrug transporter, P-glycoprotein, actively mediates cholesterol redistribution in the cell membrane". Proceedings of the National Academy of Sciences. 99 (16): 10347–10352. Bibcode:2002PNAS...9910347G. doi:10.1073/pnas.162366399. PMC 124917. PMID 12145328.