The conformational signature of β-arrestin2 predicts its trafficking and signalling functions.
The conformational signature of β-arrestin2 predicts its trafficking and signalling functions.
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DOI：
10.1038/nature17154
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发表时间：
2016-03-31
期刊：
影响因子：
64.8
通讯作者：
Luttrell LM
中科院分区：
文献类型：
--
作者：
Lee MH;Appleton KM;Strungs EG;Kwon JY;Morinelli TA;Peterson YK;Laporte SA;Luttrell LM
阻滞素是一种胞浆蛋白，调节G蛋白偶联受体的脱敏、内化、转运和信号转导。Arrestin的招募将gpcr从异源三聚体G蛋白中解偶联，并通过笼蛋白包裹的凹坑将其内化为靶点。抑制素还可以作为配体调节的支架，将多个非G蛋白效应器招募到基于GPCR的“信号体”中。虽然抑制蛋白的主导功能(S)在不同的受体之间有所不同，但不同的GPCR指定不同的arrestin功能的机制尚不清楚。使用一组分子内的闪光-Bret记者来监测arrestin3的构象变化，我们在这里展示了GPCRs施加了独特的arresin‘构象特征’，反映了受体-arrestin复合体的稳定性以及arrestin3在激活或抑制下游信号事件中的作用。这些标记的预测价值延伸到激活相同GPCR的结构不同的配体，从而使配体的固有属性反映为arrestin3构象的变化。我们的发现表明，关于配体-受体构象的信息编码在群体平均拦阻构象中，并为不同的GPCR如何将共同的效应器用于不同的目的提供了洞察。该方法可应用于功能选择性GPCR配体的表征和开发，并可用于鉴定决定Arrestin构象和功能的因素。
Arrestins are cytosolic proteins that regulate G protein-coupled receptor (GPCR) desensitization, internalization, trafficking, and signaling. Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets them for internalization via clathrin-coated pits. Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G protein effectors into GPCR-based ‘signalsomes’. While the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify divergent arrestin functions is not understood. Using a panel of intramolecular FlAsH-BRET reporters to monitor conformational changes in arrestin3, we show here that GPCRs impose distinctive arrestin ‘conformational signatures’ that reflect the stability of the receptor-arrestin complex and role of arrestin3 in activating or dampening downstream signaling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in arrestin3 conformation. Our findings demonstrate that information about ligand-receptor conformation is encoded within the population average arrestin3 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands and in identifying factors that dictate arrestin conformation and function.