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

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.
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [3] ;  [4] ; ORCiD logo [1] ;  [2] ;  [5]
  1. Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry
  2. 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.
  3. 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
  4. Hebrew Univ. of Jerusalem (Israel). School of Computer Science and Engineering, Inst. of Life Sciences
  5. 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
Publication Date:
Grant/Contract Number:
AC02-05CH11231; GM107069
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 7; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; integrative modeling; PAS domains; cryptochrome; circadian rhythms
OSTI Identifier:
1379737