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] although examples in β-strands have also been found.^[2]

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 any 5 amino acids.^[3] The CRAC motif on a transmembrane protein is preferentially located in the inner leaflet.^[4] 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.^[4]

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.^[5] However, P-gp basal ATPase activity was inhibited after cholesterol depletion by Methyl-beta-cyclodextrin, suggesting that cholesterol binding activates P-gp ATPase activity.^[5]

Not all proteins with cholesterol consensus domains are involved in cholesterol binding, however, as the motif has been found in the proteome of bacteria that lack cholesterol.^[2]

The cholesterol consensus domain should not be confused with the cholesterol consensus motif (CCM), which has the similar sequence (K/R)-X2-6-(I/V/L)-X3-(W/Y), and is found in class A G-protein coupled receptors such as the β2 adrenergic receptor.^[2]