Promotion of Myoblast Differentiation by Fkbp5 via Cdk4 Isomerization

Fkbp5 is a widely expressed peptidyl prolyl isomerase that serves as a molecular chaperone through conformational changes of binding partners. Although it regulates diverse protein functions, little is known about its roles in myogenesis. We found here that Fkbp5 plays critical roles in myoblast differentiation through two mechanisms. First, it sequesters Cdk4 within the Hsp90 storage complex and prevents the formation of the cyclin D1-Cdk4 complex, which is a major inhibitor of differentiation. Second, Fkbp5 promotes cis-trans isomerization of the Thr172-Pro173 peptide bond in Cdk4 and inhibits phosphorylation of Thr172, an essential step for Cdk4 activation. Consistent with these in vitro findings, muscle regeneration is delayed in Fkbp5^−/− mice. The related protein Fkbp4 also sequesters Cdk4 within the Hsp90 complex but does not isomerize Cdk4 or induce Thr173 phosphorylation despite its highly similar sequence. This study demonstrates protein isomerization as a critical regulatory mechanism of myogenesis by targeting Cdk4. Ruiz-Estevez et al. show that Fkbp5 inhibits Cdk4 activity by sequestering it in the Hsp90 complex and preventing phosphorylation at T172 through isomerization of P173. Lack of Cdk4 activity inhibits proliferation and promotes myogenesis. This study provides evidence that Fkbp5 functions as an isomerase necessary for myogenesis.