Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Mol Cell. 2023 Jun 1;83(11):1903-1920.e12. doi: 10.1016/j.molcel.2023.05.008.
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.
运动在许多方面有益于人体。鸢尾素由肌肉分泌，运动时增加，并传递生理益处，包括改善认知和抵抗神经退行性变。鸢尾素通过αV 整联蛋白发挥作用；然而，人们对像鸢尾素这样的小多肽如何通过整联蛋白信号传递的机制理解甚少。通过使用质谱和冷冻电镜，我们证明运动时肌肉分泌细胞外热休克蛋白 90α（eHsp90α），并激活整合素αVβ5。这使得高亲和力的鸢尾素结合和通过 Hsp90α/αV/β5 复合物进行信号转导成为可能。通过包含氢/氘交换数据，我们生成并实验验证了一个 2.98Å RMSD 鸢尾素/αVβ5 复合物对接模型。鸢尾素与αVβ5 上不同于已知配体的替代结合界面紧密结合。这些数据阐明了一种非典型机制，即像鸢尾素这样的小多肽激素可以通过整合素受体发挥作用。
