Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, India.
Biochem Biophys Res Commun. 2011 Jan 7;404(1):569-73. doi: 10.1016/j.bbrc.2010.12.031. Epub 2010 Dec 10.
G-protein coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across membranes, and represent major targets in the development of novel drug candidates in all clinical areas. Membrane cholesterol has been reported to have an important role in the function of a number of GPCRs. Several structural features of proteins, believed to result in preferential association with cholesterol, have been recognized. Cholesterol recognition/interaction amino acid consensus (CRAC) sequence represents such a motif. Many proteins that interact with cholesterol have been shown to contain the CRAC motif in their sequence. We report here the presence of CRAC motifs in three representative GPCRs, namely, rhodopsin, the β(2)-adrenergic receptor, and the serotonin(1A) receptor. Interestingly, the function of these GPCRs has been previously shown to be dependent on membrane cholesterol. The presence of CRAC motifs in GPCRs indicates that interaction of cholesterol with GPCRs could be specific in nature. Further analysis shows that CRAC motifs are inherent characteristic features of the serotonin(1A) receptor and are conserved over natural evolution. These results constitute the first report of the presence of CRAC motifs in GPCRs and provide novel insight in the molecular nature of GPCR-cholesterol interaction.
G 蛋白偶联受体 (GPCRs) 是参与跨膜信号转导的最大类分子，是所有临床领域新型药物候选物开发的主要靶点。据报道，膜胆固醇在许多 GPCR 的功能中具有重要作用。已经认识到一些被认为与胆固醇优先结合的蛋白质的结构特征。胆固醇识别/相互作用氨基酸共识 (CRAC) 序列代表了这样的基序。许多与胆固醇相互作用的蛋白质在其序列中含有 CRAC 基序。我们在这里报告了三种代表性 GPCR（视紫红质、β(2)-肾上腺素能受体和 5-羟色胺 (1A) 受体）中存在 CRAC 基序。有趣的是，这些 GPCR 的功能以前被证明依赖于膜胆固醇。GPCR 中存在 CRAC 基序表明胆固醇与 GPCR 的相互作用可能具有特异性。进一步的分析表明，CRAC 基序是 5-羟色胺 (1A) 受体的固有特征，并且在自然进化中是保守的。这些结果首次报道了 GPCR 中存在 CRAC 基序，并为 GPCR-胆固醇相互作用的分子性质提供了新的见解。
