Insulin receptor (IR) and the epidermal growth factor receptor (EGFR) were the first receptor tyrosine kinases (RTKs) to be studied in detail. Both are important clinical targets-in diabetes and cancer, respectively. They have unique extracellular domain compositions among RTKs, but share a common module with two ligand-binding leucine-rich-repeat (LRR)-like domains connected by a flexible cysteine-rich (CR) domain (L1-CR-L2 in IR/domain, I-II-III in EGFR). This module is linked to the transmembrane region by three fibronectin type III domains in IR, and by a second CR in EGFR. Despite sharing this conserved ligand-binding module, IR and EGFR family members are considered mechanistically distinct-in part because IR is a disulfide-linked (αβ)2 dimer regardless of ligand binding, whereas EGFR is a monomer that undergoes ligand-induced dimerization. Recent cryo-electron microscopy (cryo-EM) structures suggest a way of unifying IR and EGFR activation mechanisms and origins of negative cooperativity. In EGFR, ligand engages both LRRs in the ligand-binding module, "closing" this module to break intramolecular autoinhibitory interactions and expose new dimerization sites for receptor activation. How insulin binds the activated IR was less clear until now. Insulin was known to associate with one LRR (L1), but recent cryo-EM structures suggest that it also engages the second LRR (albeit indirectly) to "close" the L1-CR-L2 module, paralleling EGFR. This transition simultaneously breaks autoinhibitory interactions and creates new receptor-receptor contacts-remodeling the IR dimer (rather than inducing dimerization per se) to activate it. Here, we develop this view in detail, drawing mechanistic links between IR and EGFR.

中文翻译：

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胰岛素和表皮生长因子受体家族成员共享平行的激活机制。

胰岛素受体（IR）和表皮生长因子受体（EGFR）是第一个要详细研究的受体酪氨酸激酶（RTK）。两者都是重要的临床靶标，分别针对糖尿病和癌症。它们在RTK中具有独特的胞外域组成，但与两个配体结合亮氨酸重复序列（LRR）相似的域共享一个共同的模块，这些域通过柔性富含半胱氨酸（CR）的域（IR / L1-CR-L2）连接域，EGFR中的I-II-III）。该模块通过IR中的三个纤连蛋白III型结构域和EGFR中的第二个CR与跨膜区相连。尽管共享此保守的配体结合模块，但IR和EGFR家族成员在机械上被认为是部分不同的，因为IR是与配体结合的二硫键连接的（αβ）2二聚体，而EGFR是经历配体诱导的二聚化的单体。最近的低温电子显微镜（cryo-EM）结构提出了一种统一IR和EGFR激活机制以及负协同性起源的方法。在EGFR中，配体将两个LRR都与配体结合模块结合，“关闭”该模块以破坏分子内自抑制相互作用，并暴露新的二聚化位点以激活受体。到目前为止，胰岛素如何结合活化的IR尚不清楚。胰岛素已知与一个LRR（L1）缔合，但是最近的冷冻电磁结构表明它也与第二个LRR（尽管是间接的）结合来“封闭”与EGFR平行的L1-CR-L2模块。这种转变同时破坏了自抑制相互作用并产生了新的受体-受体接触，从而重塑了IR二聚体（而不是诱导二聚体本身）以激活它。在这里，我们详细介绍这种观点，