Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity

Domı́nguez, Isabel; Cruz-Gamero, Jose M.; Corasolla, V; Dacher, Nicolas; Rangasamy, Sampathkumar; Urbani, Andrea; Narayanan, Vinodh; Rebholz, Heike

doi:10.1007/s00439-021-02280-5

Cited by 20 publications

(49 citation statements)

References 74 publications

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“…When considering the total amount of material analyzed by LC-MS/MS for each kinase (1570 ng for CK2 WT , 1430 ng for CK2 K198R ) the overall kinase activity of CK2 K198R can be approximated at 85% of CK2 WT , thus suggesting that the OCNDS CK2 K198R mutation results in only a slight decrease in kinase activity relative to wild type CK2. This observed activity of CK2 K198R stands in contrast to previous results indicating that the mutation results in a loss of activity ( Dominguez et al, 2021 ).…”

Section: Resultscontrasting

confidence: 99%

“…Contrary to prior speculation and findings, it is clear from our experiments that the CK2 K198R mutation does not simply cause a loss of function, or an inability to recognize substrates ( Chiu et al, 2018 ; Dominguez et al, 2021 ). We demonstrate that the K198R mutation results in a substantial shift in specificity by reducing the overall preference for acidic (D/E) residues at the +1 position, and by increasing preference for glycine residues at the same position.…”

Section: Discussioncontrasting

confidence: 99%

“…We demonstrate that the K198R mutation results in a substantial shift in specificity by reducing the overall preference for acidic (D/E) residues at the +1 position, and by increasing preference for glycine residues at the same position. Differences from prior results ( Dominguez et al, 2021 ) can be attributed to the approach used. In Dominguez et al the authors utilized a single peptide, RRRADDSDDDDD, to assay the activity of CK2 and its mutant form.…”

Section: Discussionmentioning

confidence: 95%

“…Of the mutations associated with OCNDS, the mutation of lysine-198 to arginine (K198R) has been most frequently observed. The K198R mutation has been speculated to result in a loss of kinase function ( Chiu et al, 2018 ), and this speculation was more recently thought to be confirmed ( Dominguez et al, 2021 ). Interestingly however, lysine-198 is located in the activation segment of CK2 and had been previously implicated in the acidic residue preference of CK2 at the +1 position relative to the phosphoacceptor ( Sarno et al, 1997 ).…”

Section: Introductionmentioning

confidence: 97%

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The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

Caefer

Phan

Liddle

et al. 2022

Front. Mol. Biosci.

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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 CK2WT, including the first characterization of specificity for tyrosine phosphorylation activity. A second high resolution motif representing CK2K198R substrate specificity was also generated. Here we report the impact of the OCNDS associated CK2K198R 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.

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Section: Resultscontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

Caefer

Phan

Liddle

et al. 2022

Front. Mol. Biosci.

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“…Typically, the CK2α mutations occurring in OCNDS are mentioned in clinical reports together with phenotypic features ( Trinh et al, 2017 ; Akahira-Azuma et al, 2018 ; Chiu et al, 2018 ; Owen et al, 2018 ; Xu et al, 2020 ), while investigations on the protein level are rare so far. Recently, Dominguez et al (2021) observed a general loss of catalytic activity for 15 OCNDS-found CK2α mutants (among them CK2α Lys198Arg ) expressed as GST-fusion proteins in bacteria, however, only with a standard peptide substrate and without an enzymologically stringent distinction in K M - and k cat -values. Caefer et al (2021) performed a sophisticated phosphoproteomics study in a bacterial system ( Chou et al, 2012 ; Lubner et al, 2018 ) and published preliminary evidence that the critical effect of the Lys198Arg mutation might concern the substrate specificity of CK2α rather than the overall activity.…”

Section: Introductionmentioning

confidence: 99%

Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2αLys198Arg

Werner

Gast

Lindenblatt

et al. 2022

Front. Mol. Biosci.

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Specific de novo mutations in the CSNK2A1 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 CK2αLys198Arg 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 CK2αLys198Arg 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.

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Subtelomeric microdeletion in chromosome 20p13 associated with short stature

Liu,

Li,

Andersson

et al. 2024

Clinical Case Reports

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Key Clinical MessageAmong the total 10 reported cases with 20p13 microdeletion, including our patient, it is notable that 50% of patients presented a height below the 3rd percentile. We suggest that short stature is among the most common manifestations in patients with 20p13 subtelomeric microdeletion.AbstractChromosome 20p13 microdeletion occurs rarely, with only 10 reported cases. We report a 16‐year‐old male with a 1.59 Mb terminal deletion in chromosome 20p13, who presented with proportionate short stature, mild language delay, mild learning disability, and delayed puberty. The clinical phenotype associated with this deletion can exhibit clinical variability. Our patient deviates from the typical developmental and intellectual phenotype seen in the 20p13 deletion, instead displaying mild speech delay, short stature, and delayed puberty. The CSNK2A1 deletion, leading to haploinsufficiency, might be the potential mechanism. And the prominence of his proportionate short stature provides a unique perspective to review the existing literature.

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Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity

Cited by 20 publications

References 74 publications

The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2αLys198Arg

Subtelomeric microdeletion in chromosome 20p13 associated with short stature

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