A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation.

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Citation

Spengler ML, Kuropatwinski KK, Schumer M, Antoch MP

A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation.

Cell Cycle. 2009 Dec 15;8(24):4138-46. Epub 2009 Dec 8.

PubMed ID
19946213 [ View in PubMed
]
Abstract

The circadian clock regulates biological processes from gene expression to organism behavior in a precise, sustained rhythm that is generated at the unicellular level by coordinated function of interlocked transcriptional feedback loops and post-translational modifications of core clock proteins. CLOCK phosphorylation regulates transcriptional activity, cellular localization and stability; however little is known about the specific residues and enzymes involved. We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427. Mutational analysis and protein stability assays indicate that this serine cluster functions as a phospho-degron. Through the use of GSK-3 activators/inhibitors and kinase assays, we demonstrate that GSK-3beta regulates the degron site by increasing CLOCK phosphorylation/degradation, which correlates with an increase in the expression of CLOCK responsive promoters. Stabilization of phospho-deficient CLOCK delays the phase of oscillation in synchronized fibroblasts. This investigation begins the characterization of a complex phospho-regulatory site that controls the activity and degradation of CLOCK, a core transcription factor that is essential for circadian behavior.

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Polypeptides
NameUniProt ID
Glycogen synthase kinase-3 betaP49841Details