Allosteric regulation of CRYs in mammalian circadian clock

Abstract

Mammalian circadian clocks are composed of transcriptional-translational feedback loops. Transcriptional activators (BMAL1/CLOCK) form positive arm and transcriptional repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)) form the negative arm of the clock mechanism in mammals. CRYs have conserved primary (FAD binding) and secondary pockets critical to interact with different proteins. Despite high structural similarities between CRY1 and CRY2, studies suggest each CRY plays a different role in the circadian clock. For example, the binding of the CRY1 to CLOCK is regulated by a dynamic serine-rich loop (Ser-loop) around the secondary pocket. A recent report showed that a distant residue Arg-293 allosterically regulates the Ser-loop in CRY1. Here, using molecular dynamics simulations, we showed that Arg-311 to His mutation in CRY2 (homolog of Arg-293 of CRY1) had a minor effect on the allosteric path to Ser-loop.