Structure of the human protein kinase CK2 catalytic subunit CK2alpha' and interaction thermodynamics with the regulatory subunit CK2beta.
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Bischoff N, Olsen B, Raaf J, Bretner M, Issinger OG, Niefind K
Structure of the human protein kinase CK2 catalytic subunit CK2alpha' and interaction thermodynamics with the regulatory subunit CK2beta.
J Mol Biol. 2011 Mar 18;407(1):1-12. doi: 10.1016/j.jmb.2011.01.020. Epub 2011 Jan 15.
- PubMed ID
- 21241709 [ View in PubMed]
- Abstract
Protein kinase CK2 (formerly "casein kinase 2") is composed of a central dimer of noncatalytic subunits (CK2beta) binding two catalytic subunits. In humans, there are two isoforms of the catalytic subunit (and an additional splicing variant), one of which (CK2alpha) is well characterized. To supplement the limited biochemical knowledge about the second paralog (CK2alpha'), we developed a well-soluble catalytically active full-length mutant of human CK2alpha', characterized it by Michaelis-Menten kinetics and isothermal titration calorimetry, and determined its crystal structure to a resolution of 2 A. The affinity of CK2alpha' for CK2beta is about 12 times lower than that of CK2alpha and is less driven by enthalpy. This result fits the observation that the beta4/beta5 loop, a key element of the CK2alpha/CK2beta interface, adopts an open conformation in CK2alpha', while in CK2alpha, it opens only after assembly with CK2beta. The open beta4/beta5 loop in CK2alpha' is stabilized by two elements that are absent in CK2alpha: (1) the extension of the N-terminal beta-sheet by an additional beta-strand, and (2) the filling of a conserved hydrophobic cavity between the beta4/beta5 loop and helix alphaC by a tryptophan residue. Moreover, the interdomain hinge region of CK2alpha' adopts a fully functional conformation, while unbound CK2alpha is often found with a nonproductive hinge conformation that is overcome only by CK2beta binding. Taken together, CK2alpha' exhibits a significantly lower affinity for CK2beta than CK2alpha; moreover, in functionally critical regions, it is less dependent on CK2beta to obtain a fully functional conformation.