Structural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans
Structural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans
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DOI：
10.1101/2023.02.17.528932
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发表时间：
2023-09
影响因子：
16.6
通讯作者：
C. Viola;Orsolya Frittmann;H. Jenkins;Talha Shafi;P. Meyts;A. Brzozowski
中科院分区：
文献类型：
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作者：
C. Viola;Orsolya Frittmann;H. Jenkins;Talha Shafi;P. Meyts;A. Brzozowski
胰岛素相关激素通过进化上保守的胰岛素信号轴（IIS）调节后生动物的关键生命过程，从新陈代谢到生长、寿命和衰老。在人类中，IIS 轴由胰岛素、两种胰岛素样生长因子、胰岛素受体的两种亚型（hIR-A 和 -B）及其同源 IGF-1R 控制。在果蝇中，这种信号传导涉及七种胰岛素样激素 (DILP1-7) 和一个受体 (dmIR)。该报告描述了 dmIR 胞外域:DILP5 复合物的冷冻电镜结构，揭示了 dmIR 和 hIR 之间的高度结构同源性。过量的 DILP5 会产生不对称“T”构象的 dmIR 复合物，类似于在某些人类 IR 复合物中观察到的情况。然而，dmIR 以迄今为止未见的排列结合三个 DILP5 分子，也显示出 dmIR 特异性的特征。这项工作为 IR 水平上 IIS 轴的进化保护提供了结构支持，也为更好地理解重要的模式生物奠定了基础。
The insulin-related hormones regulate key life processes in Metazoa, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin signalling axis (IIS). In humans the IIS axis is controlled by insulin, two insulin-like growth factors, two isoforms of the insulin receptor (hIR-A and -B), and its homologous IGF-1R. In Drosophila, this signalling engages seven insulin-like hormones (DILP1-7) and a single receptor (dmIR). This report describes the cryoEM structure of the dmIR ectodomain:DILP5 complex, revealing high structural homology between dmIR and hIR. The excess of DILP5 yields dmIR complex in an asymmetric ‘T’ conformation, similar to that observed in some complexes of human IRs. However, dmIR binds three DILP5 molecules in a hitherto-unseen arrangement, showing also dmIR-specific features. This work adds structural support to evolutionary conservation of the IIS axis at the IR level, underpinning also a better understanding of an important model organism.