9B3S

Crystal structure of casein kinase 1 delta 1 with tethered phosphorylated tail

Summary for 9B3S

• Entry DOI: 10.2210/pdb9b3s/pdb
• Descriptor: Casein kinase I isoform delta (2 entities in total)
• Functional Keywords: kinase, serine-threonine kinase, transferase, circadian clock protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 74115.16

Authors

Harold, R.L.,Yaitanes, N.,Tripathi, S.T.,Partch, C.L. (deposition date: 2024-03-20, release date: 2024-09-25, Last modification date: 2024-10-16)

Primary citation

Harold, R.L.,Tulsian, N.K.,Narasimamurthy, R.,Yaitanes, N.,Ayala Hernandez, M.G.,Lee, H.W.,Crosby, P.,Tripathi, S.M.,Virshup, D.M.,Partch, C.L.
Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1.
Proc.Natl.Acad.Sci.USA, 121:e2415567121-e2415567121, 2024

PubMed Abstract: 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.

PubMed: 39356670
DOI: 10.1073/pnas.2415567121

Experimental method

X-RAY DIFFRACTION (2.4 Å)