Han M, Gurevich V V, Vishnivetskiy S A, Sigler P B, Schubert C
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Structure. 2001 Sep;9(9):869-80. doi: 10.1016/s0969-2126(01)00644-x.
Arrestins are responsible for the desensitization of many sequence-divergent G protein-coupled receptors. They compete with G proteins for binding to activated phosphorylated receptors, initiate receptor internalization, and activate additional signaling pathways.
In order to understand the structural basis for receptor binding and arrestin's function as an adaptor molecule, we determined the X-ray crystal structure of two truncated forms of bovine beta-arrestin in its cytosolic inactive state to 1.9 A. Mutational analysis and chimera studies identify the regions in beta-arrestin responsible for receptor binding specificity. beta-arrestin demonstrates high structural homology with the previously solved visual arrestin. All key structural elements responsible for arrestin's mechanism of activation are conserved.
Based on structural analysis and mutagenesis data, we propose a previously unappreciated part in beta-arrestin's mode of action by which a cationic amphipathic helix may function as a reversible membrane anchor. This novel activation mechanism would facilitate the formation of a high-affinity complex between beta-arrestin and an activated receptor regardless of its specific subtype. Like the interaction between beta-arrestin's polar core and the phosphorylated receptor, such a general activation mechanism would contribute to beta-arrestin's versatility as a regulator of many receptors.
抑制蛋白负责许多序列不同的G蛋白偶联受体的脱敏作用。它们与G蛋白竞争结合活化的磷酸化受体，启动受体内化，并激活其他信号通路。
为了了解受体结合的结构基础以及抑制蛋白作为衔接分子的功能，我们确定了处于胞质非活性状态的两种截短形式的牛β抑制蛋白的X射线晶体结构，分辨率达到1.9埃。突变分析和嵌合体研究确定了β抑制蛋白中负责受体结合特异性的区域。β抑制蛋白与先前解析的视紫红质抑制蛋白具有高度的结构同源性。所有负责抑制蛋白激活机制的关键结构元件都是保守的。
基于结构分析和诱变数据，我们提出了β抑制蛋白作用模式中一个以前未被认识的部分，即阳离子两亲性螺旋可能作为一种可逆的膜锚定物发挥作用。这种新的激活机制将促进β抑制蛋白与活化受体之间形成高亲和力复合物，而不管其具体亚型如何。就像β抑制蛋白的极性核心与磷酸化受体之间的相互作用一样，这种普遍的激活机制将有助于β抑制蛋白作为许多受体调节剂的多功能性。
