Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex
- University of Washington, United States
- University of Texas, Southwestern Medical Center, United States
- Kyoto Prefectural University of Medicine, Japan
- Graduate School of Natural Science and Technology, Kanazawa University, Japan
- University of Texas Southwestern Medical Center, United States
- The University of Texas Southwestern Medical Center, United States
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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© 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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Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex
eLife 3:e03674.
https://doi.org/10.7554/eLife.03674
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