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Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing
Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064333/ https://www.ncbi.nlm.nih.gov/pubmed/32101164 http://dx.doi.org/10.7554/eLife.55275 |
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author | Fribourgh, Jennifer L Srivastava, Ashutosh Sandate, Colby R Michael, Alicia K Hsu, Peter L Rakers, Christin Nguyen, Leslee T Torgrimson, Megan R Parico, Gian Carlo G Tripathi, Sarvind Zheng, Ning Lander, Gabriel C Hirota, Tsuyoshi Tama, Florence Partch, Carrie L |
author_facet | Fribourgh, Jennifer L Srivastava, Ashutosh Sandate, Colby R Michael, Alicia K Hsu, Peter L Rakers, Christin Nguyen, Leslee T Torgrimson, Megan R Parico, Gian Carlo G Tripathi, Sarvind Zheng, Ning Lander, Gabriel C Hirota, Tsuyoshi Tama, Florence Partch, Carrie L |
author_sort | Fribourgh, Jennifer L |
collection | PubMed |
description | Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1. |
format | Online Article Text |
id | pubmed-7064333 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-70643332020-03-11 Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing Fribourgh, Jennifer L Srivastava, Ashutosh Sandate, Colby R Michael, Alicia K Hsu, Peter L Rakers, Christin Nguyen, Leslee T Torgrimson, Megan R Parico, Gian Carlo G Tripathi, Sarvind Zheng, Ning Lander, Gabriel C Hirota, Tsuyoshi Tama, Florence Partch, Carrie L eLife Biochemistry and Chemical Biology Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1. eLife Sciences Publications, Ltd 2020-02-26 /pmc/articles/PMC7064333/ /pubmed/32101164 http://dx.doi.org/10.7554/eLife.55275 Text en © 2020, Fribourgh et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Fribourgh, Jennifer L Srivastava, Ashutosh Sandate, Colby R Michael, Alicia K Hsu, Peter L Rakers, Christin Nguyen, Leslee T Torgrimson, Megan R Parico, Gian Carlo G Tripathi, Sarvind Zheng, Ning Lander, Gabriel C Hirota, Tsuyoshi Tama, Florence Partch, Carrie L Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing |
title | Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing |
title_full | Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing |
title_fullStr | Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing |
title_full_unstemmed | Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing |
title_short | Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing |
title_sort | dynamics at the serine loop underlie differential affinity of cryptochromes for clock:bmal1 to control circadian timing |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064333/ https://www.ncbi.nlm.nih.gov/pubmed/32101164 http://dx.doi.org/10.7554/eLife.55275 |
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