Mu A, Thomas E Wales, Haixia Zhou, Sorin-Valeriu Draga-Coletă, Christoph Gorgulla, Katherine A Blackmore, Melanie J Mittenbühler, Caroline R Kim, Dina Bogoslavski, Qiuyang Zhang, Zi-Fu Wang, Mark P Jedrychowski, Hyuk-Soo Seo, Kijun Song, Andrew Z Xu, Luke Sebastian, Steven P Gygi, Haribabu Arthanari, Sirano Dhe-Paganon, Patrick R Griffin, John R Engen, Bruce M Spiegelman
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引用次数: 0
摘要
运动对人体有很多益处。鸢尾素由肌肉分泌,随运动而增加,并带来生理益处,包括改善认知能力和抵抗神经变性。鸢尾素通过αV整合素发挥作用;然而,人们对鸢尾素等小多肽如何通过整合素发出信号的机制了解甚少。我们利用质谱法和低温电子显微镜证明,肌肉在运动时会分泌细胞外热休克蛋白 90α(eHsp90α),并激活整合素 αVβ5。这样就能通过 Hsp90α/αV/β5 复合物与高亲和力的鸢尾素结合并发出信号。通过加入氢/氘交换数据,我们生成并通过实验验证了一个 2.98 Å RMSD 的鸢尾素/αVβ5 复合物对接模型。鸢尾素与αVβ5上的另一个界面紧密结合,该界面不同于已知配体所使用的界面。这些数据阐明了鸢尾素等小多肽激素通过整合素受体发挥作用的非规范机制。
Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α.
Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys physiological benefits, including improved cognition and resistance to neurodegeneration. Irisin acts via αV integrins; however, a mechanistic understanding of how small polypeptides like irisin can signal through integrins is poorly understood. Using mass spectrometry and cryo-EM, we demonstrate that the extracellular heat shock protein 90α (eHsp90α) is secreted by muscle with exercise and activates integrin αVβ5. This allows for high-affinity irisin binding and signaling through an Hsp90α/αV/β5 complex. By including hydrogen/deuterium exchange data, we generate and experimentally validate a 2.98 Å RMSD irisin/αVβ5 complex docking model. Irisin binds very tightly to an alternative interface on αVβ5 distinct from that used by known ligands. These data elucidate a non-canonical mechanism by which a small polypeptide hormone like irisin can function through an integrin receptor.
期刊介绍:
Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.