9rfn
Structure of protein kinase CK2alpha mutant E264D associated with the Okur-Chung Neurodevelopmental Syndrome
Structural highlights
FunctionCSK21_HUMAN Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.[1] [2] [3] [4] Publication Abstract from PubMedIn 2016, CSNK2A1, the gene which encodes the catalytic alpha-subunit of human protein kinase CK2 was linked to an autism spectrum disorder called Okur-Chung neurodevelopmental syndrome (OCNDS) for the first time. Human protein kinase CK2 is a heterotetrameric phosphotransferase with an alpha(2)beta(2) composition. To gain more insight into genotype-phenotype relationships, 42 CK2alpha variants associated with OCNDS were characterized in this study in terms of enzymatic activity using a canonical CK2 peptide substrate. Out of the 42 variants tested, 13 had no detectable enzymatic activity and 12 showed less than 10% of wild-type CK2alpha activity. The addition of the regulatory CK2beta subunit increased the activity of all active variants. Twelve variants that exhibited at least 30% wild-type enzymatic activity were chosen to determine the dissociation constants with CK2beta; highlighting that none of these mutations had an impact on the interaction of CK2alpha with CK2beta. The variants R21Q, T127M, E264D, E282K, and R333* showed no reduced activity in comparison to wild-type CK2alpha. Additionally, affinity to CK2beta and thermostability remained unaltered. K198R is the most frequent missense variant observed in OCNDS patients; thus, we performed a site-saturation mutagenesis at position K198 to elucidate what impact other variants at this position could have on enzymatic activity. Results showed that replacement of K198 by any other amino acid resulted in similar loss of activity as the prevalent K198R variant. The presented results suggest that other parameters beyond enzymatic activity, CK2beta affinity or thermostability may contribute to neurodevelopmental disorders such as OCNDS. Functional characterization of 42 CK2alpha de novo variants associated with Okur-Chung neurodevelopmental syndrome.,Gast A, Werner C, Niefind K, Jose J FEBS J. 2026 Apr 13. doi: 10.1111/febs.70538. PMID:41978434[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
