7PSU

Structure of protein kinase CK2alpha mutant K198R associated with the Okur-Chung Neurodevelopmental Syndrome

Summary for 7PSU

• Entry DOI: 10.2210/pdb7psu/pdb
• Descriptor: Casein kinase II subunit alpha, 1,2-ETHANEDIOL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: protein kinase ck2, casein kinase 2, csnk2a1 mutant k198r, okur-chung neurodevelopmental syndrome, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 96309.94

Authors

Werner, C.,Gast, A.,Lindenblatt, D.,Nickelsen, K.,Niefind, K.,Jose, J.,Hochscherf, J. (deposition date: 2021-09-23, release date: 2022-03-23, Last modification date: 2024-01-31)

Primary citation

Werner, C.,Gast, A.,Lindenblatt, D.,Nickelsen, A.,Niefind, K.,Jose, J.,Hochscherf, J.
Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2 alpha Lys198Arg.
Front Mol Biosci, 9:831693-831693, 2022

PubMed Abstract: Specific mutations in the gene, which encodes CK2α, the catalytic subunit of protein kinase CK2, are considered as causative for the Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS is a rare congenital disease with a high phenotypic diversity ranging from neurodevelopmental disabilities to multi-systemic problems and characteristic facial features. A frequent OCNDS mutation is the exchange of Lys198 to Arg at the center of CK2α's P+1 loop, a key element of substrate recognition. According to preliminary data recently made available, this mutation causes a significant shift of the substrate specificity of the enzyme. We expressed the CK2α recombinantly and characterized it biophysically and structurally. Using isothermal titration calorimetry (ITC), fluorescence quenching and differential scanning fluorimetry (Thermofluor), we found that the mutation does not affect the interaction with CK2β, the non-catalytic CK2 subunit, and that the thermal stability of the protein is even slightly increased. However, a CK2α crystal structure and its comparison with wild-type structures revealed a significant shift of the anion binding site harboured by the P+1 loop. This observation supports the notion that the Lys198Arg mutation causes an alteration of substrate specificity which we underpinned here with enzymological data.

PubMed: 35445078
DOI: 10.3389/fmolb.2022.831693

Experimental method

X-RAY DIFFRACTION (1.77 Å)