Mol. Cell. 66, 447–457 (2017)

The bHLH-PAS transcription factor BMAL1 (brain and muscle ARNT-like 1) is a circadian activator that ensures proper periodicity. BMAL1 activity is mediated by the direct interaction of transcriptional activators such as CBP–p300 and the PER–CRY feedback repressors. In particular, CRY1 and p300 compete for binding at the transactivation domain (TAD) to dictate circadian periodicity; mutations in this region can alter the period length. Using NMR analysis of the TAD C-terminal region, Gustafson et al. found that the W624–P625 imide bond, which is conserved in other BMAL1 homologs, undergoes isomerization between cis and trans conformations. Mutation of either W624 or P625 to alanine or substitution of W624 with tyrosine to decrease aromaticity locked BMAL1 in the trans conformation, resulting in a shorter period. Conversely, replacing P625 with a bulky proline analog trapped the cis isomer. In wild-type BMAL1, the isomerization between cis and trans was very slow and required the presence of peptidyl-prolyl isomerases such as cyclophilins to accelerate this conversion; inhibition of cyclophilin using cyclosporine A also increased the circadian period. As the cis and trans isomers exhibited similar binding to CBP and CRY, further studies will be needed to reveal the mechanism by which bond isomerization alters periodicity.