Molecular basis for multimerization in the activation of the epidermal growth factor receptor
Molecular basis for multimerization in the activation of the epidermal growth factor receptor
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DOI：
10.7554/elife.14107
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发表时间：
2016-03-28
期刊：
影响因子：
7.7
通讯作者：
Kuriyan, John
中科院分区：
文献类型：
--
作者：
Huang, Yongjian;Bharill, Shashank;Kuriyan, John
表皮生长因子受体（EGFR）被二聚化激活，但激活也产生高阶多聚体，其性质和功能尚不清楚。我们利用单分子分析表征了配体诱导的EGFR二聚化和多聚化，并表明多聚化可以被细胞外模块的特定区域IV的突变阻断。这些突变减少了EGFR c端尾部的自磷酸化，减弱了由EGFR募集的磷脂酰肌醇3-激酶的磷酸化。EGFR的催化活性是通过一个激酶结构域被另一个激酶结构域的变构激活而开启的，我们表明，如果这仅限于二聚体，那么尾部靠近激酶结构域的位点仅在一个亚基中被磷酸化。我们提出了一种通过配体结合二聚体自结合的EGFR多聚的结构模型，其中大多数激酶结构域被协同激活，从而促进尾部磷酸化。
The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.