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, Singapore.; Merck Sharp & Dohme International GmBH (Singapore), Neuros, Singapore 138665, Singapore., Narasimamurthy R; Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Yaitanes N; Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064., Ayala Hernandez MG; 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-National University of Singapore Medical School, Singapore 169857, Singapore.; 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.; HHMI, University of California, Santa Cruz, CA 95064.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 08; Vol. 121 (41), pp. e2415567121. Date of Electronic Publication: 2024 Oct 02.
DOI:	10.1073/pnas.2415567121
Abstrakt:	Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (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, δ1 and δ2, 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 whether the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and hydrogen/deuterium exchange mass spectrometry, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 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 the 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: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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