EGFR in a sticky situation: probing structural transitions in dimerized receptors

描述（由申请人提供）：令人信服的证据表明，目前表皮生长因子受体（EGFR）信号传导的结构模型是不完整的，因为它们不能解释细胞中表现出负协同配体结合的无活性、预组装受体二聚体的群体。因此，EGFR信号传导涉及受体二聚体的配体依赖性变构调节，而不是通过简单的配体诱导的二聚化进行。该提案描述了我将如何（i）获得预组装EGFR二聚体的彻底结构理解，（ii）确定在“关闭”和“打开”状态之间切换受体二聚体的构象变化，以及（iii）研究备受讨论的致癌突变和配体特异性EGFR“打开”状态差异调节信号输出的可能性。我的初步数据显示，高度同源的C。Elegans EGFR是组成型二聚体，这避免了与人EGFR相关的技术挑战，并提供了回答这些重要机制问题的独特和直接的机会。由于过度的EGFR信号转导驱动了许多人类癌症，因此这些结果将为设计新一代“更智能”的EGFR靶向癌症疗法提供概念框架。

DESCRIPTION (provided by applicant): Compelling evidence suggests that current structural models of epidermal growth factor receptor (EGFR) signaling are incomplete, as they cannot account for the population of inactive, pre-assembled receptor dimers in cells that exhibit negatively cooperative ligand binding. Thus, rather than proceeding through simple ligand- induced dimerization, EGFR signaling involves the ligand-dependent allosteric regulation of receptor dimers. This proposal describes how I will (i) obtain a thorough structural understanding of pre-assembled EGFR dimers, (ii) identify the conformational changes that switch receptor dimers between the 'off' and 'on' states, and (iii) investigate the much-discussed possibilities of oncogenic mutation- and ligand-specific 'on' states of EGFR that differentially modulate signaling output. My preliminary data shows that the highly-homologous C. elegans EGFR is constitutively dimeric, which circumvents technical challenges associated with human EGFR and provides a unique and straightforward opportunity to answer these important mechanistic questions. Since excessive EGFR signaling drives many human cancers, the results will provide the conceptual framework for designing a new generation of 'smarter' EGFR-targeted cancer therapies.