CK2: A protein kinase in need of control

Protein kinase CK2 is a heterotetrameric alpha(2)beta(2) Ser/Thr protein ki nase with some features unusual among the eukaryotic protein kinases: (1) C K2 recognizes phosphoacceptor sites specified by several acidic determinant s; (2) CK2 can use both ATP and GTP as phosphoryl donors; and (3) the regul atory properties of CK2 are poorly understood; it is insensitive to any kno wn second messenger and displays high basal activity. To gain insight into CK2 regulation and to understand its unusual properties, site-directed muta genesis experiments on both subunits and Xray crystallographic studies of t he catalytic alpha-subunit were performed. The noncatalytic beta-subunit ha s at least three functions: (1) it protects the alpha-subunit against denat uring agents or conditions; (2) it alters the substrate specificity of the alpha-subunit; and (3) it modulates the activity of the enzyme, i.e., depen ding on the substrate, it increases or decreases the activity of the alpha- subunit. Mutagenesis experiments revealed that an acidic stretch between am ino acids 55 and 64 has a down regulatory and autoinhibitory function. Muta tional analysis of the alpha-subunit has revealed a network of unique basic residues that are responsible for the recognition of phosphoacceptor subst rates and for down regulation by the beta-subunit and by polyanionic inhibi tors. The resolution of the crystal structure of Zea mays CK2 alpha-subunit has disclosed the structural features that are responsible for high basal activity and for unusual response to nucleotide analogs. The increasing kno wledge of CK2 structure-function relationships will allow the design of hig hly selective inhibitors of this pleiotropic kinase with oncogenic potentia l. (C) 1999 Elsevier Science Inc. All rights reserved.