Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex

Shannon N. Nangle, Clark Rosensweig, Nobuya Koike, Hajime Tei, Joseph S. Takahashi, Carla B. Green, Ning Zheng

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere03656
Pages (from-to)1-14
Number of pages14
JournaleLife
Volume3
Issue numberAugust2014
DOIs
StatePublished - Aug 15 2014

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Cryptochromes
Period Circadian Proteins
Circadian Clocks
Zinc Fingers
Periodicity
Ligases
Ubiquitin
Clocks
Conformations
Zinc
Crystal structure
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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex. / Nangle, Shannon N.; Rosensweig, Clark; Koike, Nobuya; Tei, Hajime; Takahashi, Joseph S.; Green, Carla B.; Zheng, Ning.

In: eLife, Vol. 3, No. August2014, e03656, 15.08.2014, p. 1-14.

Research output: Contribution to journalArticle

Nangle, SN, Rosensweig, C, Koike, N, Tei, H, Takahashi, JS, Green, CB & Zheng, N 2014, 'Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex', eLife, vol. 3, no. August2014, e03656, pp. 1-14. https://doi.org/10.7554/eLife.03674
Nangle, Shannon N. ; Rosensweig, Clark ; Koike, Nobuya ; Tei, Hajime ; Takahashi, Joseph S. ; Green, Carla B. ; Zheng, Ning. / Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex. In: eLife. 2014 ; Vol. 3, No. August2014. pp. 1-14.
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