1 Ocak 2020 Dergi makalesi Açık Erişim

Gul, Seref; Aydin, Cihan; Ozcan, Onur; Gurkan, Berke; Surme, Saliha; Baris, Ibrahim; Kavakli, Ibrahim Halil

Dublin Core

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  <dc:creator>Gul, Seref</dc:creator>
  <dc:creator>Aydin, Cihan</dc:creator>
  <dc:creator>Ozcan, Onur</dc:creator>
  <dc:creator>Gurkan, Berke</dc:creator>
  <dc:creator>Surme, Saliha</dc:creator>
  <dc:creator>Baris, Ibrahim</dc:creator>
  <dc:creator>Kavakli, Ibrahim Halil</dc:creator>
  <dc:date>2020-01-01</dc:date>
  <dc:description>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.</dc:description>
  <dc:identifier>https://aperta.ulakbim.gov.trrecord/9225</dc:identifier>
  <dc:identifier>oai:zenodo.org:9225</dc:identifier>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>http://www.opendefinition.org/licenses/cc-by</dc:rights>
  <dc:source>JOURNAL OF BIOLOGICAL CHEMISTRY 295(50) 17187-17199</dc:source>
  <dc:title>The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm</dc:title>
  <dc:type>info:eu-repo/semantics/article</dc:type>
  <dc:type>publication-article</dc:type>
</oai_dc:dc>