Researcher:
Gürkan, Berke

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Master Student

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Berke

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Gürkan

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Gürkan, Berke

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20201

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Researcher Of Publications: search.filters.isAuthorOfPublication.2091b15e-6d3b-4d0d-8f00-7bb3add04a98

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    PublicationOpen Access
    The Arg293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm
    (American Society for Biochemistry and Molecular Biology (ASBMB), 2020) Aydın, Cihan; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Gürkan, Berke; Sürme, Saliha; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; 111629; 40319
    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 rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1-/-Cry2-/-double 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.