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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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.
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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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