Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein Kinase 1.

Autor:	Harold RL; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Tulsian NK; Department of Biological Sciences, National University of Singapore, Singapore 117543.; MSD International GmBH (Singapore), Neuros, 8 Biomedical Grove, Singapore, 138665., Narasimamurthy R; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857., Yaitanes N; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Hernandez MGA; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Lee HW; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Crosby P; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Tripathi SM; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Virshup DM; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857.; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710., Partch CL; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064.; Center for Circadian Biology, University of California San Diego, La Jolla, CA 92093.; Lead contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 29. Date of Electronic Publication: 2024 Jul 29.
DOI:	10.1101/2023.04.24.538174
Abstrakt:	Casein kinase 1 δ (CK1δ) controls essential biological processes including circadian rhythms and Wnt signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ 1 and δ 2 , are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C-termini (XCT), but with marked changes in potential phosphorylation sites. Here we test if the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and HDX-MS, we show that the δ 1 XCT is preferentially phosphorylated by the kinase and the δ 1 tail makes more extensive interactions across the kinase domain. Mutation of δ1 -specific XCT phosphorylation sites increases kinase activity both in vitro and in cells and leads to changes in circadian period, similar to what is reported in vivo . Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ . These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase. Competing Interests: Declaration of interests The authors declare no competing interests.
Databáze:	MEDLINE
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