Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor.
Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor.
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作者：
Li J;Wu J;Hall C;Bai XC;Choi E
胰岛素受体（IR）和胰岛素样生长因子1受体（IGF 1 R）控制代谢稳态和细胞生长与增殖。IR和IGF 1 R在脱辅基状态下形成类似的二硫键连接的同源二聚体;然而，它们的配体结合特性和活性状态下的结构显著不同。IR和IGF 1 R的α链C端二硫键连接片段（αCTs）控制着配体结合的协同性，调节受体的活化。尽管如此，二硫键连接的α CT在IR和IGF 1 R激活中作用的分子基础仍不清楚。在这里，我们报告了全长小鼠IGF 1 R/IGF 1和IR/胰岛素复合物的冷冻电镜结构，其中修饰的α CT具有增加的灵活性。与具有单个IGF 1结合的I“形不对称IGF 1 R二聚体不同，具有增强的α CT柔性的IGF 1 R可以形成具有两个IGF 1结合的T形对称二聚体。同时，非共价连接的αCTs的IR主要采用与四个胰岛素结合的不对称构象，这与T形对称IR不同。通过基于细胞的实验，我们进一步证明了IGF 1 R和修饰的αCTs的IR都不能有效地激活下游信号传导。总的来说，我们的研究表明，二硫键连接的α CT的一定结构刚性对于最佳IR和IGF 1 R信号传导激活至关重要。
The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.