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.
Highlights
Life on Earth evolved a self-sustaining molecular timing system that synchronizes cellular activities with the solar day
The mammalian circadian clock operates through an auto-regulatory transcription– translation feedback loop composed of four core components—the transcriptional activator proteins, CLOCK and BMAL1, and the transcriptional repressors, Periods (PERs) and Cryptochromes (CRYs)
PERs have been suggested to act through multiple mechanisms, including mediating CRY nuclear entry, coupling CRYs to CLOCK-BMAL1, and competing with FBXL3 to stabilize CRYs
Summary
Life on Earth evolved a self-sustaining molecular timing system that synchronizes cellular activities with the solar day. This endogenous clockwork prepares an organism for periodic environmental fluctuations and coordinates numerous physiological and behavioral processes (Reppert and Weaver, 2002). The heterodimeric CLOCK and BMAL1 complex acts as the positive arm of the loop by recognizing E-box elements and promoting the expression of clock-controlled genes, including Per, Per, Cry, and Cry. The PER and CRY proteins function as the negative arm of the loop by blocking the activity of CLOCK-BMAL1 and inhibiting the transcription of their own and all other clock-controlled genes. The cyclic accumulation, localization, and degradation of the PER and CRY proteins are necessary to manifest a 24-hr rhythm (Lowrey and Takahashi, 2011)
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