Isoform- specific C- terminal phosphorylation drives autoinhibition of Casein kinase 1

• 成果类型: Article
• 署名作者: Harold, Rachel L.; Tulsian, Nikhil K.; Narasimamurthy, Rajesh; Yaitanes, Noelle; Hernandez, Maria G. Ayala; Lee, Hsiau-Wei; Crosby, Priya; Tripathi, Sarvind M.; Virshup, David M.; Partch, Carrie L.
• 署名单位: University of California System; University of California Santa Cruz; National University of Singapore; National University of Singapore; Duke University; University of California System; University of California San Diego; Howard Hughes Medical Institute; University of California System; University of California Santa Cruz
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13005
• DOI: 10.1073/pnas.2415567121
• 发表日期: 2024-10-08
• 关键词: hydrogen-deuterium exchange; i epsilon; cki-delta; hdx-ms; Mutation; proteins; clock

摘要

Casein kinase 1 delta (CK1 delta) controls essential biological processes including circadian rhythms and wingless- related integration site (Wnt) signaling, but how its activity is regulated is not well understood. CK1 delta is inhibited by autophosphorylation of its intrinsically disordered C- terminal tail. Two CK1 splice variants, delta 1 and delta 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 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 delta 1 XCT is preferentially phosphorylated by the kinase and the delta 1 tail makes more extensive interactions across 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 anion- binding sites around the CK1 active site, demonstrating a common mode of controls the activity of this essential kinase.