PXD026766

PXD026766 is an original dataset announced via ProteomeXchange.

Title	Autophosphorylation of the CK1 kinase domain regulates enzyme activity and substrate specificity
Description	CK1 enzymes are conserved, acidophilic serine/threonine kinases with a variety of critical cellular functions; their misregulation contributes to cancer, neurodegenerative diseases, and sleep phase disorders. Here, we describe a new mechanism of CK1 regulation conserved from yeast to human – autophosphorylation of a threonine in the mobile L-EF loop proximal to the active site – that inhibits kinase activity. Consequently, yeast and human CK1 enzymes with phosphoablating mutations at this site are hyperactive in vitro. We used quantitative phosphoproteomics to show that disruption of this regulatory mechanism rewires CK1 signaling in Schizosaccharomyces pombe. In accord, we found that a known CK1 pathway, a mitotic checkpoint, is downregulated in these mutants, while new pathways that confer heat shock resistance and suppress meiotic transcripts are upregulated. Molecular dynamics simulations demonstrated that phosphorylation on the L-EF loop alters the conformation of the substrate docking site, and we propose that this affects which CK1 substrates can be phosphorylated. Due to the functional importance of the L-EF loop, which is unique to the CK1 family of kinases, this mechanism is likely to regulate the majority of CK1 enzymes in vivo.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:02:36.608.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jose Navarrete Perea
SpeciesList	scientific name: Schizosaccharomyces pombe 927; NCBI TaxID: 1264690;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-17 21:40:11	ID requested
1	2023-07-20 10:42:58	announced
⏵ 2	2023-11-14 09:02:44	announced	2023-11-14: Updated project metadata.

Cullati SN, Chaikuad A, Chen JS, Gebel J, Tesmer L, Zhubi R, Navarrete-Perea J, Guillen RX, Gygi SP, Hummer G, D, ö, tsch V, Knapp S, Gould KL, Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes. Mol Cell, 82(11):2006-2020.e8(2022) [pubmed]

submitter keyword: casein kinase 1,CK1, S. pombe, substrate specificity, kinase regulation

Kathleen L. Gould, Ph.D.
contact affiliation	Louise B. McGavock Professor Department of Cell and Developmental Biology Senior Associate Dean for Biomedical Research, Education and Career Development. Vanderbilt University School of Medicine
contact email	kathy.gould@vanderbilt.edu
lab head
Jose Navarrete Perea
contact affiliation	Harvard Medical School
contact email	Jose_Navarrete-Perea@hms.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026766
     1. Label: PRIDE project
     2. Name: Autophosphorylation of the CK1 kinase domain regulates enzyme activity and substrate specificity