Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90a

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 aV 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 90a (eHsp90a) is secreted by muscle with exercise and activates integrin aV85. This allows for high-affinity irisin binding and signaling through an Hsp90a/aV/85 complex. By including hydrogen/deuterium exchange data, we generate and experimentally validate a 2.98 A RMSD iri-sin/aV85 complex docking model. Irisin binds very tightly to an alternative interface on aV85 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.