Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex

Abstract
Article and author information
Metrics

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.

Article and author information

Author details

Shannon N Nangle

University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Clark Rosensweig

University of Texas, Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Nobuya Koike

Kyoto Prefectural University of Medicine, Kyoto, Japan

Competing interests
The authors declare that no competing interests exist.
Hajime Tei

Graduate School of Natural Science and Technology, Kanazawa University, Ishikawa, Japan

Competing interests
The authors declare that no competing interests exist.
Joseph S Takahashi

University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Carla B Green

The University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Ning Zheng

University of Washington, Seattle, United States

For correspondence
nzheng@uw.edu

Competing interests
The authors declare that no competing interests exist.

Copyright

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.