Arrestin interactions with G protein-coupled receptors.
Arrestin interactions with G protein-coupled receptors.
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DOI：
10.1007/978-3-642-41199-1_2
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发表时间：
2014-01-01
影响因子：
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通讯作者：
Hoffmann, Carsten
中科院分区：
文献类型：
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作者：
Lohse, Martin J;Hoffmann, Carsten
G蛋白偶联受体（GPCR）是抑制蛋白的主要相互作用伴侣。视觉抑制蛋白，抑制蛋白1和抑制蛋白4，在生理上仅与非常少的受体结合，即，视紫红质和颜色视蛋白。相比之下，普遍表达的非视觉变体β-arrestin 1和2以相当非特异性的方式与大量受体结合。这种结合需要两个触发器，激动剂激活和受体磷酸化的G蛋白偶联受体激酶（GRK）。这两个触发因子由抑制蛋白的两个不同区域介导，即蛋白质核心中的“磷酸化传感器”和定义不太明确的“激活传感器”。结合似乎主要以1：1的化学计量发生，涉及GPCR的N-末端结构域，但另外，当活性受体丰富时，第二个GPCR可能松散地结合到C-末端结构域。它使受体稳定在活性构象中，并且还诱导抑制蛋白的构象变化，其涉及两个结构域相对于彼此的旋转加上极性核心的变化。这种构象变化似乎允许与其他下游蛋白质相互作用。后者的相互作用，主要表现为β-arrestins，触发受体内化，以及一些非经典的信号pathways.Open问题关注的确切化学计量的相互作用，可能的特异性方面的类型的激动剂和GRK参与，选择性调节下游信号（=偏置信号），并选择使用这些机制作为治疗靶点。
G-protein-coupled receptors (GPCRs) are the primary interaction partners for arrestins. The visual arrestins, arrestin1 and arrestin4, physiologically bind to only very few receptors, i.e., rhodopsin and the color opsins, respectively. In contrast, the ubiquitously expressed nonvisual variants beta-arrestin1 and 2 bind to a large number of receptors in a fairly nonspecific manner. This binding requires two triggers, agonist activation and receptor phosphorylation by a G-protein-coupled receptor kinase (GRK). These two triggers are mediated by two different regions of the arrestins, the "phosphorylation sensor" in the core of the protein and a less well-defined "activation sensor." Binding appears to occur mostly in a 1:1 stoichiometry, involving the N-terminal domain of GPCRs, but in addition a second GPCR may loosely bind to the C-terminal domain when active receptors are abundant.Arrestin binding initially uncouples GPCRs from their G-proteins. It stabilizes receptors in an active conformation and also induces a conformational change in the arrestins that involves a rotation of the two domains relative to each other plus changes in the polar core. This conformational change appears to permit the interaction with further downstream proteins. The latter interaction, demonstrated mostly for beta-arrestins, triggers receptor internalization as well as a number of nonclassical signaling pathways.Open questions concern the exact stoichiometry of the interaction, possible specificity with regard to the type of agonist and of GRK involved, selective regulation of downstream signaling (=biased signaling), and the options to use these mechanisms as therapeutic targets.