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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Publications

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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Project description:Src family kinases are often overexpressed and constitutively active in cancer cells, where they represent promising targets for therapeutic intervention. In myeloid hematopoietic cells, Hck, Lyn, and Fgr are associated with both chronic and acute forms of myeloid leukemia. All three of these kinases are expressed in acute myeloid leukemia (AML), where high-level expression correlates with poor survival. The pyrrolopyrimidine Src-family kinase inhibitor A-419259 (also known as RK-20449) has been shown to significantly inhibit patient-derived AML bone marrow cell growth in immunocompromised mice. Recent work has identified an N-phenylbenzamide kinase inhibitor, known as TL02-59, which potently inhibited Fgr kinase activity in vitro and reversed orthotopic engraftment of AML cells in the bone marrow and spleen of immunocompromised mice following oral administration. The inhibitory mechanism of this compound with Fgr or other Src-family members has not been reported. Both wild-type Fgr and a tail mutant (i.e., replacement of Tyr527 with Phe) were shown to produce equal numbers of transformed colonies when expressed in rodent fibroblasts, whereas wild-type Hck transforming activity was completely repressed. In both Hck and Fgr, however, the tail tyrosine residue was shown to be phosphorylated, and hydrogen deuterium exchange mass spectrometry (HDX MS) of near-full-length Fgr was consistent with the closed conformation in solution, with the SH3 domain bound to the SH2-kinase linker and the tail bound to SH2. Here we present the first X-ray crystal structures of near-full-length Fgr bound to the ATP site inhibitors A-419259 and TL02-59. Structural changes induced by the inhibitors in the crystalline state were validated in solution using HDX MS, with A-419259 stabilizing the closed conformation and TL02-59 enhancing exposure of the SH3 domain to solvent. These new structures help to explain the constitutive activity of wild-type Fgr in cells as well as its unique sensitivity to TL02-59, which is currently in development for AML and other maladies.

Dataset Information

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

Publications

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

Similar Datasets

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