Dataset Information

Irisin acts through its integrin receptor in a novel two-step process

ABSTRACT: Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys many 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 extracellular heat-shock protein 90α (eHsp90α) is secreted by muscle with exercise and acts as a required cofactor that “opens” the integrin αVβ5 structure to allows for high affinity irisin binding and signaling through an eHsp90α/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 involved in its interaction with known ligands. These data together elucidate a non-canonical mechanism by which a small polypeptide hormone like irisin can function through integrins.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John R. Engen

LAB HEAD: John R. Engen

PROVIDER: PXD035397 | Pride | 2023-06-04

REPOSITORIES: Pride

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Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α.

A Mu M Wales Thomas E TE Zhou Haixia H Draga-Coletă Sorin-Valeriu SV Gorgulla Christoph C Blackmore Katherine A KA Mittenbühler Melanie J MJ Kim Caroline R CR Bogoslavski Dina D Zhang Qiuyang Q Wang Zi-Fu ZF Jedrychowski Mark P MP Seo Hyuk-Soo HS Song Kijun K Xu Andrew Z AZ Sebastian Luke L Gygi Steven P SP Arthanari Haribabu H Dhe-Paganon Sirano S Griffin Patrick R PR Engen John R JR Spiegelman Bruce M BM

Molecular cell 20230601 11

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 exerc ...[more]

PMID: 37267907

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