A structural competition involving WDR5 times circadian oscillations

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 PER1 WIN /WDR5/RbBP5 WBM - and PER1/WDR5/CRY complexes as potential transition states between activating MLL1 WIN /WDR5/RbBP5 WBM - 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.