EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization
EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization
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DOI：
10.1016/s1097-2765(03)00047-9
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发表时间：
2003-02-01
期刊：
影响因子：
16
通讯作者：
Lemmon, MA
中科院分区：
文献类型：
--
作者：
Ferguson, KM;Berger, MB;Lemmon, MA
表皮生长因子（EGF）受体是ErbB（HER）家族受体酪氨酸激酶（RTK）的原型，其调节细胞生长和分化，并与许多人类癌症有关。EGF通过诱导621个氨基酸的EGF受体胞外区的二聚化来激活其受体。我们描述了2.8埃分辨率的晶体结构，这整个细胞外区域（sEGFR）在未激活状态。该结构揭示了一种自动抑制的配置，其中最近在活化的sEGFR结构中鉴定的二聚化界面被分子内相互作用完全封闭。为了激活受体，EGF结合必须促进暴露这种二聚化界面的大结构域重排。这与其他RTK激活机制形成鲜明对比，并提出了设计ErbB受体拮抗剂的新方法。
Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER)family receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation and are implicated in many human cancers. EGF activates its receptor by inducing dimerization of the 621 amino acid EGF receptor extracellular region. We describe the 2.8 Angstrom resolution crystal structure of this entire extracellular region (sEGFR) in an unactivated state. The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions. To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface. This contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists.