Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation.

Autor: Ibrahim H; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Reus P; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Mundorf AK; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Grothoff AL; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Rudenko V; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Buschhaus C; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Stefanski A; Biologisch-Medizinisches Forschungszentrum, Molecular Proteomics Laboratory, University of Düsseldorf, 40225 Düsseldorf, Germany., Berleth N; Institute of Molecular Medicine I, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Stork B; Institute of Molecular Medicine I, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Stühler K; Biologisch-Medizinisches Forschungszentrum, Molecular Proteomics Laboratory, University of Düsseldorf, 40225 Düsseldorf, Germany.; Institute of Molecular Medicine I, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Kalfalah F; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany., Reinke H; Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Apr 06; Vol. 22 (7). Date of Electronic Publication: 2021 Apr 06.
DOI: 10.3390/ijms22073787
Abstrakt: 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.
Databáze: MEDLINE
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