The crystal structure of a fully active form of human protein kinase CK2 (casein kinase 2) consisting of two C‐terminally truncated catalytic and two regulatory subunits has been determined at 3.1 Å resolution (Protein Data Bank code: 1JWH). In the CK2 complex the regulatory subunits form a stable dimer linking the two catalytic subunits, which make no direct contact with one another. Each catalytic subunit interacts with both regulatory chains, predominantly via an extended C‐terminal tail of the regulatory subunit. The CK2 structure is consistent with its constitutive activity and with a flexible role of the regulatory subunit as a docking partner for various protein kinases. Furthermore it shows an inter‐domain mobility in the catalytic subunit known to be functionally important in protein kinases and detected here for the first time directly within one crystal structure.
Protein kinase CK2 (formerly referred to as casein kinase II) is an evolutionary conserved, ubiquitous protein kinase. There are two paralog catalytic subunits, i.e. alpha (A1) and alpha' (A2). The alpha and alpha' subunits are linked to two beta subunits to produce a heterotetrameric structure. The catalytic alpha subunits are distantly related to the CMGC subfamily of kinases, such as the Cdk kinases. There are some peculiarities associated with protein kinase CK2, which are not found with most other protein kinases: (i) the enzyme is constitutively active, (ii) it can use ATP and GTP and (iii) it is found elevated in most tumors investigated and rapidly proliferating tissues. With the elucidation of the structure of the catalytic subunit, it was possible to explain why the enzyme is constitutively active [1] and why it can bind GTP [2]. Considerable information on the potential roles of CK2 in various disease processes including cancer has been gained in recent years, and the present review may help to further elucidate its aberrant role in many disease states. Its peculiar structural features [3-9] may be advantageous in designing tailor-made compounds with the possibility to specifically target this protein kinase [10]. Since not all the aspects of what has been published on CK2 can be covered in this review, we would like to recommend the following reviews; (i) for general information on CK2 [11-18] and (ii) with a focus on aberrant CK2 [19-22].
Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory  subunit, CK2, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2 gene in mice leads to postimplantation lethality. Mutant embryos were reduced in size at embryonic day 6.5 (E6.5). They did not exhibit signs of apoptosis but did show reduced cell proliferation. Mutant embryos were resorbed at E7.5. In vitro, CK2 ؊/؊ morula development stopped after the blastocyst stage. Attempts to generate homozygous embryonic stem (ES) cells failed. By using a conditional knockout approach, we show that lack of CK2 is deleterious for mouse ES cells and primary embryonic fibroblasts. This is in contrast to what occurs with yeast cells, which can survive without functional CK2. Thus, our study demonstrates that in mammals, CK2 is essential for viability at the cellular level, possibly because it acquired new functions during evolution.Protein kinase CK2 is a pleiotropic and highly conserved protein kinase with more than 300 substrates described to date. It seems to be involved in controlling a large panel of normal cellular functions such as gene expression, protein synthesis, cell cycle, and proliferation, as well as pathological processes such as carcinogenesis and viral tumorigenesis (12, 33). Recently, its function in protecting cells against apoptosis has been reported (1).CK2 is a tetrameric holoenzyme generally composed of two catalytic subunits, ␣ and ␣Ј, and two regulatory  subunits which combine to form an ␣␣Ј 2 , ␣ 2  2 , or ␣Ј 2  2 heterotetramer. The catalytic CK2 subunits ␣ and ␣Ј belong to the eukaryotic protein kinase superfamily. In contrast, the regulatory  subunit is a unique protein encoded by a single gene in mammals (3) and does not belong to a known protein family.CK2 has several functions in the holoenzyme complex. Reconstitution experiments with recombinant purified subunits have demonstrated that CK2 modulates the activity of CK2. Depending on the substrate, CK2 activates or downregulates the activity of the catalytic subunit (24). CK2 also confers stability to the holoenzyme complex (18) and seems to mediate interaction with a number of substrates (19).The crystal structure elucidations of the isolated CK2 subunit (5) and of the holoenzyme complex (28) indicate that the  subunit exists as a dimer and is the building block of the CK2 holoenzyme bridging the two catalytic subunits. The crystal structure is also consistent with the suggested flexible role of the  subunit as a docking partner for other protein kinases and other interacting partners in the cell (28).Functional and biochemical studies have indicated that fractions of both the catalytic and regulatory subunits may exist separately. A population of CK2␣ that binds to protein phosphatase 2A is free of CK2 (16). Moreover, CK2 fractions devoid of the catalytic subunit, but probably involved in complexes with other prote...
Corresponding authorsCK2α is the catalytic subunit of protein kinase CK2, an acidophilic and constitutively active eukaryotic Ser/Thr kinase involved in cell proliferation. A crystal structure, at 2.1 Å resolution, of recombinant maize CK2α (rmCK2α) in the presence of ATP and Mg 2⍣ , shows the enzyme in an active conformation stabilized by interactions of the N-terminal region with the activation segment and with a cluster of basic residues known as the substrate recognition site. The close interaction between the N-terminal region and the activation segment is unique among known protein kinase structures and probably contributes to the constitutively active nature of CK2. The active centre is occupied by a partially disordered ATP molecule with the adenine base attached to a novel binding site of low specificity. This finding explains the observation that CK2, unlike other protein kinases, can use both ATP and GTP as phosphorylating agents.
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