Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor
Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor
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DOI：
10.1016/s1097-2765(03)00487-8
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发表时间：
2003-12-01
期刊：
影响因子：
16
通讯作者：
Hubbard, SR
中科院分区：
文献类型：
--
作者：
Hu, JJ;Liu, J;Hubbard, SR
衔接蛋白APS是胰岛素受体的底物，并将受体活化与Cbl的磷酸化偶联以促进葡萄糖摄取。与激活的胰岛素受体的相互作用是由APS的Src同源2（SH 2）结构域介导的。在这里，我们提出的晶体结构的APS SH 2结构域的复合物与磷酸化酪氨酸激酶结构域的胰岛素受体。该结构揭示了APS SH 2结构域的一种新的二聚体构型，其中每个原聚体的C-末端一半在结构上与常规的单体SH 2结构域不同。APS SH 2二聚体接合两个激酶分子，其中激酶活化环的pTyr-1158结合在SH 2结构域的典型磷酸酪氨酸结合口袋中，第二磷酸酪氨酸pTyr-1162由β链D中的两个赖氨酸残基配位。该结构提供了胰岛素激活其二聚体受体后的初始下游募集事件之一的分子可视化。
The adaptor protein APS is a substrate of the insulin receptor and couples receptor activation with phosphorylation of Cbl to facilitate glucose uptake. The interaction with the activated insulin receptor is mediated by the Src homology 2 (SH2) domain of APS. Here, we present the crystal structure of the APS SH2 domain in complex with the phosphorylated tyrosine kinase domain of the insulin receptor. The structure reveals a novel dimeric configuration of the APS SH2 domain, wherein the C-terminal half of each protomer is structurally divergent from conventional, monomeric SH2 domains. The APS SH2 dimer engages two kinase molecules, with pTyr-1 158 of the kinase activation loop bound in the canonical phosphotyrosine binding pocket of the SH2 domain and a second phosphotyrosine, pTyr-1162, coordinated by two lysine residues in beta strand D. This structure provides a molecular visualization of one of the initial downstream recruitment events following insulin activation of its dimeric receptor.