9hk5
Structure of a mutant of human protein kinase CK2alpha' that equals its isoenzyme CK2alpha in affinity to the regulatory subunit CK2beta
Structural highlights
FunctionCSK22_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] Publication Abstract from PubMedProtein kinase CK2 (casein kinase 2) mainly exists as heterotetrameric holoenzyme with two catalytic subunits (CK2alpha or CK2alpha') bound to a homodimer of non-catalytic subunits (CK2beta). With CSNK2A1 and CSNK2A2, the human genome contains two paralogs encoding catalytic CK2 subunits. Both gene products, called CK2alpha and CK2alpha', strongly interact with CK2beta. An earlier report that CK2alpha' has a lower CK2beta affinity than CK2alpha is confirmed via isothermal titration calorimetry in this study. Furthermore, we show with a fluorescence-anisotropy assay that a CK2beta-competitive peptide binds less strongly to CK2alpha' than to CK2alpha. The reason for the reduced affinity of CK2alpha' to CK2beta and CK2beta competitors is puzzling: both isoenzymes have identical amino acid compositions at their CK2beta interfaces, but the beta4beta5 loop, a component of this interface, is conformationally less adaptable in CK2alpha' than in CK2alpha due to intramolecular constraints. To release these constraints, we constructed a CK2alpha' mutant that was equalized to CK2alpha at the backside of the beta4beta5 loop. Concerning thermostability, affinity to CK2beta or CK2beta competitors and 3D-structure next to the beta4beta5 loop, this CK2alpha' mutant is more similar to CK2alpha than to its own wild-type, suggesting a critical role of the beta4beta5 loop adaptability for CK2beta affinity. A CK2alpha' mutant indicating why CK2alpha and CK2alpha', the isoforms of the catalytic subunit of human protein kinase CK2, deviate in affinity to CK2beta.,Werner C, Eimermacher S, Harasimowicz H, Fischer D, Pietsch M, Niefind K Biol Chem. 2025 Apr 14. doi: 10.1515/hsz-2024-0157. PMID:40223482[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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