The Okur-Chung Neurodevelopmental Syndrome Mutation CK2 K198R Leads to a Rewiring of Kinase Specificity.

Autor:	Caefer DM; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States., Phan NQ; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States., Liddle JC; Center for Open Research Resources and Equipment, Proteomics and Metabolomics Facility, University of Connecticut, Storrs, CT, United States., Balsbaugh JL; Center for Open Research Resources and Equipment, Proteomics and Metabolomics Facility, University of Connecticut, Storrs, CT, United States., O'Shea JP; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States., Tzingounis AV; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States., Schwartz D; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2022 Apr 19; Vol. 9, pp. 850661. Date of Electronic Publication: 2022 Apr 19 (Print Publication: 2022).
DOI:	10.3389/fmolb.2022.850661
Abstrakt:	Okur-Chung Neurodevelopmental Syndrome (OCNDS) is caused by heterozygous mutations to the CSNK2A1 gene, which encodes the alpha subunit of protein kinase CK2. The most frequently occurring mutation is lysine 198 to arginine (K198R). To investigate the impact of this mutation, we first generated a high-resolution phosphorylation motif of CK2 WT , including the first characterization of specificity for tyrosine phosphorylation activity. A second high resolution motif representing CK2 K198R substrate specificity was also generated. Here we report the impact of the OCNDS associated CK2 K198R mutation. Contrary to prior speculation, the mutation does not result in a complete loss of function, but rather shifts the substrate specificity of the kinase. Broadly speaking the mutation leads to 1) a decreased preference for acidic residues in the +1 position, 2) a decreased preference for threonine phosphorylation, 3) an increased preference for tyrosine phosphorylation, and 4) an alteration of the tyrosine phosphorylation specificity motif. To further investigate the result of this mutation we have developed a probability-based scoring method, allowing us to predict shifts in phosphorylation in the K198R mutant relative to the wild type kinase. As an initial step we have applied the methodology to the set of axonally localized ion channels in an effort to uncover potential alterations of the phosphoproteome associated with the OCNDS disease condition. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Caefer, Phan, Liddle, Balsbaugh, O’Shea, Tzingounis and Schwartz.)
Databáze:	MEDLINE
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