Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1

Michael, Alicia K.; Fribourgh, Jennifer L.; Chelliah, Yogarany; Sandate, Colby R.; Hura, Greg L.; Schneidman-Duhovny, Dina; Tripathi, Sarvind M.; Takahashi, Joseph S.; Partch, Carrie L.

doi:10.1073/pnas.1615310114

Title: Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1

Journal Article · Mon Jan 30 23:00:00 EST 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1615310114 · OSTI ID:1379737

Michael, Alicia K. ^[1]; Fribourgh, Jennifer L. ^[1]; Chelliah, Yogarany ^[2]; Sandate, Colby R. ^[1]; Hura, Greg L. ^[3]; Schneidman-Duhovny, Dina ^[4];

^[1]; Takahashi, Joseph S. ^[2]; Partch, Carrie L. ^[5]

Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Neuroscience; Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Howard Hughes Medical Inst.
Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division
Hebrew Univ. of Jerusalem (Israel). School of Computer Science and Engineering, Inst. of Life Sciences
Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry; Univ. of California, San Diego, CA (United States). Center for Circadian Biology

The basic helix-loop-helix PAS domain (bHLH-PAS) transcription factor CLOCK:BMAL1 (brain and muscle Arnt-like protein 1) sits at the core of the mammalian circadian transcription/translation feedback loop. Precise control of CLOCK:BMAL1 activity by coactivators and repressors establishes the ~24-h periodicity of gene expression. Formation of a repressive complex, defined by the core clock proteins cryptochrome 1 (CRY1):CLOCK:BMAL1, plays an important role controlling the switch from repression to activation each day. Here in this paper, we show that CRY1 binds directly to the PAS domain core of CLOCK: BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solution X-ray scattering studies unambiguously position a key loop of the CLOCK PAS-B domain in the secondary pocket of CRY1, analogous to the antenna chromophore-binding pocket of photolyase. CRY1 docks onto the transcription factor alongside the PAS domains, extending above the DNA-binding bHLH domain. Single point mutations at the interface on either CRY1 or CLOCK disrupt formation of the ternary complex, highlighting the importance of this interface for direct regulation of CLOCK:BMAL1 activity by CRY1.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1379737

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 7 Vol. 114; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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