Casein kinase 1a mediates a two-step subunit remodeling mechanism to regulate the FRQ-FRH circadian clock complex

🥈 Top 2% JournalJan 8, 2026Nature communications

Casein kinase 1a controls a two-step change in clock protein parts to regulate the FRQ-FRH circadian clock complex

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Abstract

FRH may decode the time-dependent phosphorylation state of FRQ by remodeling the FRQ-FRH complex.

FRQ's negative feedback loop in Neurospora is regulated by FRH and CK1a through phosphorylation.
CK1a hyperphosphorylates FRQ, which is crucial for its role in maintaining the circadian clock.
The remodeling of the FRQ-FRH complex occurs in two steps, initially keeping FRQ inactive.
Slow phosphorylation leads to the release of FRH, activating FRQ by exposing a binding site for WCC.
The delayed release of the second FRH promotes nuclear export and degradation of FRQ.

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The circadian clock of Neurospora operates through a negative feedback loop in which FREQUENCY (FRQ), along with FRQ-interacting RNA helicase (FRH) and casein kinase 1a (CK1a), inhibits its transcriptional activator, WHITE COLLAR COMPLEX (WCC), via phosphorylation. CK1a, anchored to FRQ, hyperphosphorylates FRQ at its intrinsically disordered regions in a slow, temperature-independent manner, forming a module suited for molecular timekeeping. However, the molecular processes triggered by FRQ's hyperphosphorylation have remained unclear. Here we show that FRH, the folded binding partner of disordered FRQ, decodes FRQ's time-dependent phosphorylation state by triggering a two-step remodeling of the FRQ-FRH complex: initially, two FRH molecules bind a FRQ dimer, keeping it inactive by blocking its interaction with WCC. Slow phosphorylation eventually triggers the dissociation of one FRH, thereby activating the complex by exposing a WCC-binding site. Due to the slow and stochastic nature of phosphorylation, the release of the second FRH occurs with a delay, promoting nuclear export and subsequent degradation of FRQ. This ensures precise activation and inactivation of FRQ and positions FRH as a hub for decoding temporal phosphorylation information.

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