Universität zu Köln

Werner, Christian, Gast, Alexander, Lindenblatt, Dirk, Nickelsen, Anna, Niefind, Karsten ORCID: 0000-0002-0183-6315, Jose, Joachim ORCID: 0000-0002-0666-2676 and Hochscherf, Jennifer ORCID: 0000-0002-4412-7391 (2022). Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2 alpha(Lys198Arg). Front. Mol. Biosci., 9. LAUSANNE: FRONTIERS MEDIA SA. ISSN 2296-889X

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Abstract

Specific de novo mutations in the CSNK2A1 gene, which encodes CK2 alpha, 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 CK2 alpha ' 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 CK2 alpha(Lys198Arg) 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 CK2 beta, the non-catalytic CK2 subunit, and that the thermal stability of the protein is even slightly increased. However, a CK2 alpha(Lys198Arg) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Werner, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Gast, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindenblatt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Nickelsen, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED Jose, Joachim UNSPECIFIED orcid.org/0000-0002-0666-2676 UNSPECIFIED Hochscherf, Jennifer UNSPECIFIED orcid.org/0000-0002-4412-7391 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-665339
DOI:	10.3389/fmolb.2022.831693
Journal or Publication Title:	Front. Mol. Biosci.
Volume:	9
Date:	2022
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	2296-889X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-KINASE CK2; CATALYTIC SUBUNIT; CASEIN KINASE-2; BISUBSTRATE INHIBITORS; CRYSTAL-STRUCTURE; CK2-ALPHA; CELL; ABNORMALITIES; LOCALIZATION; RECOGNITION Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66533