Interaction of G protein coupled receptors and cholesterol
Interaction of G protein coupled receptors and cholesterol
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DOI：
10.1016/j.chemphyslip.2016.04.006
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发表时间：
2016-09-01
影响因子：
3.4
通讯作者：
Gimpl, Gerald
中科院分区：
文献类型：
--
作者：
Gimpl, Gerald
G蛋白偶联受体（GPCRs）是真核细胞中最大的受体超家族。由于它们的七个跨膜螺旋，这些蛋白质的大部分嵌入在富含胆固醇的质膜双层中。因此，GPCR总是接近胆固醇。它们中的一些在功能上依赖于胆固醇的特定存在。在过去的几年里，受体结构已经取得了巨大的进展。虽然胆固醇以外的亲脂性配体已被证明可以结合在螺旋束内部或受体-脂质界面处，但胆固醇的结合位点是单个跨膜螺旋或两个或更多个跨膜螺旋之间的凹槽。尚未观察到对两个膜瓣叶之一的明显偏好。毫不奇怪，许多疏水残基（主要是亮氨酸和异亮氨酸）被发现参与胆固醇结合。在大多数情况下，胆固醇的粗糙p面接触跨膜螺旋束，而不是周围的脂质基质。胆固醇的极性羟基位于水膜界面附近，与受体环区域的残基形成潜在的氢键。尽管在β 2AR的情况下检测到一个指定为CCM位点的典型基序作为特异性胆固醇结合位点，但在具有相同基序的其他GPCR中未发现该位点被胆固醇占据。胆固醇受体相互作用可以增加受体结构的紧密性，并且能够增强对活性或非活性受体状态的构象稳定性。总的来说，目前所有的数据表明，GPCR中胆固醇相互作用位点的可塑性很高。(C)2016爱思唯尔爱尔兰有限公司版权所有。
G protein coupled receptors (GPCRs) form the largest receptor superfamily in eukaryotic cells. Owing to their seven transmembrane helices, large parts of these proteins are embedded in the cholesterol-rich plasma membrane bilayer. Thus, GPCRs are always in proximity to cholesterol. Some of them are functionally dependent on the specific presence of cholesterol. Over the last years, enormous progress on receptor structures has been achieved. While lipophilic ligands other than cholesterol have been shown to bind either inside the helix bundle or at the receptor-lipid interface, the binding site of cholesterol was either a single transmembrane helix or a groove between two or more transmembrane helices. A clear preference for one of the two membrane leaflets has not been observed. Not surprisingly, many hydrophobic residues (primarily leucine and isoleucine) were found to be involved in cholesterol binding. In most cases, the rough p-face of cholesterol contacted the transmembrane helix bundle rather than the surrounding lipid matrix. The polar hydroxy group of cholesterol was localized near the water-membrane interface with potential hydrogen bonding to residues in receptor loop regions. Although a canonical motif, designated as CCM site, was detected as a specific cholesterol binding site in case of the beta 2AR, this site was not found to be occupied by cholesterol in other GPCRs possessing the same motif. Cholesterol receptor interactions can increase the compactness of the receptor structure and are able to enhance the conformational stability towards active or inactive receptor states. Overall, all current data suggest a high plasticity of cholesterol interaction sites in GPCRs. (C) 2016 Elsevier Ireland Ltd. All rights reserved.