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bioRxiv · 10.1101/2023.06.05.543739

A structural competition involving WDR5 times circadian oscillations

Boergel, A.·Rawleigh, A.·Conrady, M.·Hof, F.·Ricci, K.·Brown, S.·Wolf, E.
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Abstract

In the mammalian circadian clock, the transcription factor BMAL1/CLOCK cycles between an active state recruiting co-activators like MLL1, and repressed states associated with the clock proteins Period1/2 (PER1/2) and Cryptochrome1/2 (CRY1/2). The MLL1 complex component WDR5 was also found in a repressive PER complex, but the roles of WDR5-PER interactions are unknown. Here we show that WDR5 directly binds to the C-terminal CRY binding domain (CBD) regions of PER1 and PER2. PER2 binds WDR5 via a WDR5 binding (WBM) motif within the PER2/CRY interface, imposing a molecular choice between PER2/WDR5- and PER2/CRY complexes. PER1 predominantly binds WDR5 via a WDR5 interacting (WIN) motif outside the CBD and exhibits a 15-fold higher WDR5 affinity than PER2. Thereby PER1 can form trimeric PER1WIN/WDR5/RbBP5WBM - and PER1/WDR5/CRY complexes as potential transition states between activating MLL1WIN/WDR5/RbBP5WBM - and repressive PER/CRY complexes. Overexpressing WDR5 in mammalian cells increases the circadian amplitude, whereas a compound targeting the WIN motif binding site of WDR5 weakens PER1-WDR5 interactions and shortens the circadian oscillation period by 2 to 3 hours. Together, our studies uncover WDR5 as direct PER interaction partner at the interface between active- and repressed states of BMAL1/CLOCK and suggest a functional role of WDR5 and its WIN site interactions in the mammalian clock by both enhancing circadian oscillations and creating a temporal delay.

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Boergel, A., Rawleigh, A., Conrady, M., Hof, F., Ricci, K., Brown, S., Wolf, E.. 2023-06-05. A structural competition involving WDR5 times circadian oscillations. https://doi.org/10.1101/2023.06.05.543739

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