1. Structural Biology and Molecular Biophysics

Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex

  1. Shannon N Nangle
  2. Clark Rosensweig
  3. Nobuya Koike
  4. Hajime Tei
  5. Joseph S Takahashi
  6. Carla B Green
  7. Ning Zheng  Is a corresponding author
  1. University of Washington, United States
  2. University of Texas, Southwestern Medical Center, United States
  3. Kyoto Prefectural University of Medicine, Japan
  4. Graduate School of Natural Science and Technology, Kanazawa University, Japan
  5. University of Texas Southwestern Medical Center, United States
  6. The University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.03674
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  1. Shannon N Nangle
  2. Clark Rosensweig
  3. Nobuya Koike
  4. Hajime Tei
  5. Joseph S Takahashi
  6. Carla B Green
  7. Ning Zheng
(2014)
Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex
eLife 3:e03674.
https://doi.org/10.7554/eLife.03674
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Abstract

The mammalian circadian clock is driven by a transcriptional-translational feedback loop, which produces robust 24-hr rhythms. Proper oscillation of the clock depends on the complex formation and periodic turnover of the Period and Cryptochrome proteins, which together inhibit their own transcriptional activator complex, CLOCK-BMAL1. We determined the crystal structure of the CRY-binding domain (CBD) of PER2 in complex with CRY2 at 2.8 Å resolution. PER2-CBD adopts a highly extended conformation, embracing CRY2 with a sinuous binding mode. Its N-terminal end tucks into CRY adjacent to a large pocket critical for CLOCK-BMAL1 binding, while its C-terminal half flanks the CRY2 C-terminal helix and sterically hinders the recognition of CRY2 by the FBXL3 ubiquitin ligase. Unexpectedly, a strictly conserved intermolecular zinc finger, whose integrity is important for clock rhythmicity, further stabilizes the complex. Our structure-guided analyses show that these interspersed CRY-interacting regions represent multiple functional modules of PERs at the CRY-binding interface.

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Author details

  1. Shannon N Nangle

    University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Clark Rosensweig

    University of Texas, Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Nobuya Koike

    Kyoto Prefectural University of Medicine, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Hajime Tei

    Graduate School of Natural Science and Technology, Kanazawa University, Ishikawa, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Joseph S Takahashi

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Carla B Green

    The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ning Zheng

    University of Washington, Seattle, United States
    For correspondence
    nzheng@uw.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Louis Ptáček, University of California, San Francisco, United States

Version history

  1. Received: June 12, 2014
  2. Accepted: August 14, 2014
  3. Accepted Manuscript published: August 15, 2014 (version 1)
  4. Version of Record published: September 9, 2014 (version 2)

Copyright

© 2014, Nangle et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shannon N Nangle
  2. Clark Rosensweig
  3. Nobuya Koike
  4. Hajime Tei
  5. Joseph S Takahashi
  6. Carla B Green
  7. Ning Zheng
(2014)
Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex
eLife 3:e03674.
https://doi.org/10.7554/eLife.03674

Share this article

https://doi.org/10.7554/eLife.03674

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