Dergi makalesi Açık Erişim
Gul, Seref; Aydin, Cihan; Ozcan, Onur; Gurkan, Berke; Surme, Saliha; Baris, Ibrahim; Kavakli, Ibrahim Halil
{ "DOI": "10.1074/jbc.RA120.014333", "abstract": "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.", "author": [ { "family": "Gul", "given": " Seref" }, { "family": "Aydin", "given": " Cihan" }, { "family": "Ozcan", "given": " Onur" }, { "family": "Gurkan", "given": " Berke" }, { "family": "Surme", "given": " Saliha" }, { "family": "Baris", "given": " Ibrahim" }, { "family": "Kavakli", "given": " Ibrahim Halil" } ], "container_title": "JOURNAL OF BIOLOGICAL CHEMISTRY", "id": "9225", "issue": "50", "issued": { "date-parts": [ [ 2020, 1, 1 ] ] }, "page": "17187-17199", "title": "The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm", "type": "article-journal", "volume": "295" }
Görüntülenme | 18 |
İndirme | 4 |
Veri hacmi | 1.0 kB |
Tekil görüntülenme | 17 |
Tekil indirme | 4 |