The EMBO journalNov 21, 2008

Phosphorylation controls WHITE COLLAR protein location, an important step in the body’s daily rhythm feedback

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

Disruption of protein phosphatase 4 (PP4) in Neurospora results in short period rhythms with low amplitude.

PP4 regulates the phosphorylation and stability of the FREQUENCY (FRQ) protein, a key component of the circadian clock.
PP4 dephosphorylates and activates the WHITE COLLAR complex (WCC), which is crucial for circadian feedback regulation.
Unlike another phosphatase (PP2A), PP4 primarily facilitates the entry of WCC into the nucleus.
Protein kinase A (PKA) inhibits the nuclear localization of WCC, impacting its function in the circadian cycle.
FRQ-dependent WCC phosphorylation leads to its localization in the cytoplasm, contributing to feedback inhibition.

Simplified

Reversible protein phosphorylation has critical functions in the eukaryotic circadian negative feedback loops. In Neurospora, the FREQUENCY protein closes the circadian negative feedback loop by promoting the phosphorylation of its transcription activator, the WHITE COLLAR complex (WCC) and consequently inhibiting WCC activity. Here we show that protein phosphatase 4 is a novel component of the Neurospora clock by regulating both processes of the circadian negative feedback loop. The disruption of pp4 results in short period rhythms with low amplitude. In addition to its role in regulating FRQ phosphorylation and stability, PP4 also dephosphorylates and activates WCC. In contrast to PP2A, another phosphatase that activates WCC, PP4 has a major function in promoting nuclear entry of WCC. PKA, a WC kinase, inhibits WC nuclear localization. Furthermore, the FRQ-dependent WC phosphorylation promotes WCC cytosolic localization. Together, these results revealed WCC nucleocytoplasmic shuttling as an important step in the circadian negative feedback process and delineated the FRQ-dependent WCC inhibition as a two-step process: the inhibition of WCC DNA-binding activity followed by sequestration of WCC into the cytoplasm.

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Phosphorylation controls WHITE COLLAR protein location, an important step in the body’s daily rhythm feedback

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