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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation
Author
Ibrahim, Hussam 1   VIAFID ORCID Logo  ; Reus, Philipp 1   VIAFID ORCID Logo  ; Mundorf, Anna Katharina 1 ; Grothoff, Anna-Lena 1 ; Rudenko, Valerie 1 ; Buschhaus, Christina 1 ; Stefanski, Anja 2 ; Berleth, Niklas 3 ; Stork, Björn 3   VIAFID ORCID Logo  ; Stühler, Kai 4 ; Kalfalah, Faiza 1 ; Reinke, Hans 1   VIAFID ORCID Logo 

 Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany; [email protected] (H.I.); [email protected] (P.R.); [email protected] (A.K.M.); [email protected] (A.-L.G.); [email protected] (V.R.); [email protected] (C.B.); [email protected] (F.K.) 
 Biologisch-Medizinisches Forschungszentrum, Molecular Proteomics Laboratory, University of Düsseldorf, 40225 Düsseldorf, Germany; [email protected] (A.S.); [email protected] (K.S.) 
 Institute of Molecular Medicine I, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany; [email protected] (N.B.); [email protected] (B.S.) 
 Biologisch-Medizinisches Forschungszentrum, Molecular Proteomics Laboratory, University of Düsseldorf, 40225 Düsseldorf, Germany; [email protected] (A.S.); [email protected] (K.S.); Institute of Molecular Medicine I, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany; [email protected] (N.B.); [email protected] (B.S.) 
First page
3787
Publication year
2021
Publication date
2021
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2548692411
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.