Abstract
Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.
Highlights
GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1) is linked to the molecular circadian oscillator as a component of cytoplasmic
It has been suggested that GAPVD1 might play a role in the assembly, accumulation, trafficking, or nuclear entry of PER complexes, since knockdown of GAPVD1 lengthens the circadian period of cultured cells and GAPVD1 must, interfere with the molecular clockwork [3]
Our study extends this hypothesis by providing evidence that the PER complex can impact the function of GAPVD1 by regulating GAPVD1 phosphorylation
Summary
The mammalian circadian system is synchronized to the environment by a light-responsive master clock in the hypothalamus that transmits timing information to peripheral oscillators via neuronal and endocrine pathways [1]. Rhythmicity of the master clock and peripheral clocks is generated by a molecular oscillator mechanism that exists in basically all cells of the body. The central working principle of the molecular oscillator is a negative feedback loop of the transcriptional repressor proteins period (PER) and cryptochrome (CRY). Their expression is driven by heterodimers of the transcriptional activator aryl hydrocarbon receptor nuclear translocator-like protein 1
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