The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Oct 8, 2020The Journal of biological chemistry

Arg-293 in Cryptochrome1 helps control how it binds to CLOCK protein in the body’s daily rhythm

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Abstract

The p.Arg293His CRY1 variant is associated with a shortened circadian period in a double knockout mouse embryonic fibroblast cell line.

CRY1 and CRY2 are components of circadian clocks, with CRY1 having a higher binding affinity to the BMAL1/CLOCK complex than CRY2.
The serine-rich loop of CRYs is regulated by Arg-293 of CRY1, which is affected by a specific genetic variant.
The p.Arg293His variant leads to reduced repressor activity on BMAL1/CLOCK-driven transcription.
In the absence of PER2, the variant exhibits a lower affinity for the BMAL1/CLOCK complex compared to normal CRY1.
Molecular dynamics simulations indicate that the p.Arg293His variant decreases the dynamicity of the serine-rich loop, influencing communication pathways.

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Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box-driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rareSNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in adouble knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm. CRY1Cry1Cry2 -/--/-

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The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Abstract

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