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New Publication from Brunner Group: Casein kinase 1a mediates a two-step subunit remodeling mechanism to regulate the FRQ- FRH circadian clock complex
Date: January 8, 2026Published: January 08, 2026.
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 COL-
LAR COMPLEX (WCC), via phosphorylation. CK1a, anchored to FRQ, hyper-
phosphorylates 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 hyper-
phosphorylation have remained unclear. Here we show that FRH, the folded
binding partner of disordered FRQ, decodes FRQ’s time-dependent phos-
phorylation state by triggering a two-step remodeling of the FRQ-FRH com-
plex: 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 phos-
phorylation information.
Carolin Schunke, Bianca Ruppert, Linda Lauinger, Sabine Schultz,
Axel C. R. Diernfellner & Michael Brunner.
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 COL-
LAR COMPLEX (WCC), via phosphorylation. CK1a, anchored to FRQ, hyper-
phosphorylates 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 hyper-
phosphorylation have remained unclear. Here we show that FRH, the folded
binding partner of disordered FRQ, decodes FRQ’s time-dependent phos-
phorylation state by triggering a two-step remodeling of the FRQ-FRH com-
plex: 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 phos-
phorylation information.
Carolin Schunke, Bianca Ruppert, Linda Lauinger, Sabine Schultz,
Axel C. R. Diernfellner & Michael Brunner.
