Background: Irisin, which corresponds to the FNDC5 receptor ectodomain, is a purported exercise-induced myokine produced by cleavage. Results: Irisin forms an extensive intersubunit ␤-sheet dimer with an FNIII-like fold. Conclusion: Irisin forms a continuous ␤-sheet dimer not observed previously for any FNIII protein and may be representative of a new FNIII class. Significance: The preformed irisin dimer suggests mechanisms for ligand and receptor activation.

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