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A Zinc Ribbon Motif Is Essential for the Formation of Functional Tetrameric Protein Kinase CK2

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Protein kinase CK2 plays an essential role in the regulation of many cellular functions. The enzyme is an heterotetrameric complex formed by the association of two catalytic α/α' subunits with two regulatory β subunits. High-resolution structure of the CK2β subunit revealed the presence of a zinc binding motif made by three-stranded antiparallel β sheets and two “knuckles” (Cys-X4-Cys and Cys-X2-Cys) contained in the invariant motif CPX3C-X22-CPXC. This zinc binding motif belongs to the sub-family of zinc ribbon domains. CK2β exist as a dimer in which the zinc ribbon motif makes many hydrophobic interactions with the zinc ribbon motif of the other monomer forming the protein-protein interface. Importantly, functional and biochemical studies have indicated that the integrity of the zinc binding motif which is pivotal in the formation of the CK2β homodimer, is also instrumental for the regulatory functions of this important protein.


CK2, protein kinase CK2 (formely known as casein kinase II); Cys, cysteine; Val, valine; Pro,proline; Leu, leucine; Ileu, isoleucine; Gly, glycine, Lys, lysine; Tyr, tyrosine; KDa, kilodalton.

Protein phosphorylation is a major mechanism for the regulation of fundamental cellular processes.1 Among the hundred of protein kinases encoded by the genome of eukaryotic cells, the Ser/Thr protein kinase CK2 (formely called casein kinase II) represents an essential component of this family of regulatory enzymes.2-5 The broad spectrum of protein substrates which are phosphorylated by CK2 underscores the functional importance of this protein kinase in the regulation of many cellular functions.5

Protein kinase CK2 exibits a high degree of conservation of amino acid sequence between evolutionarily distant organisms such as yeast, Drosophila and human.2 When purified from many sources, CK2 appears as a tetrameric enzyme (with a molecular mass of 130 kDa), composed of two types of structurally analogous catalytic α (42 to 44 kDa) and α'(38 kDa) subunits and two regulatory β (27 kDa) subunits which associate to form stable α2β2, αα'β2, or α'2β2 structures. The lethal phenotype resulting from disruption of the α subunit in yeast can be rescued by expression of Drosophila α showing that the catalytic subunit is functionally interchangeable between distantly related species.6 In male mice, CK2α' is preferencially expressed in late stages of spermatogenesis and disruption of its gene results in infertility owing to defective spermatogenesis.7 However, the apparently normal embryonic development of CK2α' knockout mice argues again for a strong functional overlap of both CK2 isoforms. RNA-mediated interference in Caenorhabditis elegans has shown that inhibition of the CK2β gene leads to embryonic lethality.8 Similarly, disruption of the CK2β subunit in mice leads to a cell-autonomous defect and early embryonic lethality.9 Thus, the production of both the α and β subunits of CK2 appears to be required for cell survival.

Mounting evidence suggest that CK2 is a component of regulatory protein kinase networks that are involved in various aspects of transformation and cancer. Targetted overexpression of CK2α in T cells and mammary glands of transgenic mice leads to lymphomagenesis and mammary tumorigenesis, respectively.10,11 A number of studies have also shown that in all human cancers that have been examined, CK2 activity is consistently enhanced suggesting that the kinase plays a role in cell proliferation but also participates in the transduction of cell survival signals.12 Finally, the involvement of CK2 in viral infection and oncogenesis has been demonstrated.3

Structural and Regulatory Features

Several recent reports have described specific structural aspects of the CK2 subunits and their functional properties providing long-awaited insights into a potential modus operandi of this pivotal protein kinase.

In many organisms as well as in humans several isoforms of the catalytic subunit of CK2 have been identified.13-16 Although closely related, they are in fact the products of different genes. The crystal structure of the catalytic a subunit from Zea mays has shown the common bilobal architecture described for protein kinases. More importantly, this study provided clues for the apparent constitutive activity of the enzyme and for the fact that this kinase can use GTP as well as ATP as phosphate donors.17

Distinct isoforms of CK2 regulatory subunits exist in S. cerevisiae, A. thaliana and in D. melanogaster. Surprisingly, in mammals, this subunit is encoded by a single gene. On the basis of sequence comparisons, CK2β does not share similarity with any known protein. However, CK2β exhibits remarkable conservation between species suggesting that this subunit plays important roles in cellular functions. This contention is illustrated by the demonstration that the expression of CK2β is essential for cell proliferation and survival in D. melanogaster18 and in mice.9

Overall Folding Properties of CK2β

The 1.7 Å resolution structure of a C-terminally truncated form of CK2β that was determined by X-ray crystallography demonstrated that two different crystal forms of the protein contain two monomers in the asymetric unit (fig. 1A). The number of contacts and extent of interactions between monomers reflect a physiological self-association and the crystal structure is in accord with the native dimeric state of CK2β in solution.19 Each monomer is an ovoid-shaped molecule containing six a helices and three β strands. The overall topology showed no structural homology with other known proteins. However the global fold comprises two separately identifiable domains that are packed closely together. Domain I (residues 1-104) is entirely a-helical (α1, α2, α3, α4 and α5). Helices α4 and α5 are forming a 95° angle of an unusual arrangement which ressembles the “L” letter. In contrast, helices α1, α2, α3, α4 wrap around helix forming a protuding acidic loop. Domain II (residues 105-161) exhibits a three-stranded antiparallel β-sheet (β1, β2 and β3) in which a zinc ion located between the α5 and α6 helices is tetrahedrally coordinated by four cysteines, (Cys 109, Cys 114, Cys 137 and Cys 140). Helix α6 (residues 163-170) makes contacts with both β1 and helix α5. The structure lack the C-terminal domain that contains the major site of association with the catalytic subunit. However, residues 170-177 which are part of the α-β subunit interface extend away from the bulk of the protein (see below). Two CK2β monomers pack against each other generating a crab-shaped molecule in which the zinc finger motif present in domain II mediates the highly stable dimerization of the protein (fig. 1A,B).

Figure 1. Ribbon representations of the CK2β dimer.

Figure 1

Ribbon representations of the CK2β dimer. The β strands are shown as pink arrows. The α helices are represented as green coils, loops as brown lines and the acidic loop as dashed brown lines. The zinc atoms and cysteine ligands (more...)

The Acidic Binding Groove

A representation of the molecular surface of CK2β shows that the two domain I of the dimer generate an extended acidic groove formed by helices α1 and α3, an acidic loop (residues 55-64) and the N-terminus of helix α4. The groove is 35Å long, 7 Å wide and 4.5 Å deep (fig. 2A). Remarkably, the size of the groove and the acidic side chains that line it creates a continuous negatively charged surface around the CK2β dimer, suggesting that this protuding region represents a binding pocket for basic ligands (fig. 2B). Interestingly, it has been observed that this isolated region of CK2β exhibited an autonomous binding activity for polyamines reflecting a functional folding of this region of the protein.20 Based on its similarity to the clusters of acidic amino acids that are typically observed in CK2 substrates, it has been proposed that this acidic segment 55DLEPDEELED64 is reminiscent of the autoinhibitory sequences that have been identified in a number of other protein kinases.4 Indeed, this acidic stretch was previously proposed to represent a regulatory region involved in the down regulation of CK2 activity,21 and in its stimulation by polybasic ligands.20

Figure 2. The electrostatic potential of the molecular surface of the N-terminal region of CK2β defines an acidic groove.

Figure 2

The electrostatic potential of the molecular surface of the N-terminal region of CK2β defines an acidic groove. (A) Modelization of polyamine-CK2β contacts. The interaction of a spermine molecule with the CK2β molecule was modelized (more...)

The Zinc Ribbon Motif

Among the 6 cysteines present in the primary structure of the human CK2β subunit, only Cys 109, Cys 114, Cys 137 and Cys 140 located in domain II are invariant in different species. The crystal structure shows that these cysteine residues are indeed involved in a zinc binding motif. There are several types of zinc binding motifs, categorized by the nature and spacing of their Zn2+ -chelating residues.22-24 In the CK2β structure, the motif is made by three-stranded antiparallel β sheets (β1, β2, and β3) but unlike the classical zinc finger, no a helix is observed. The Zn2+ binding site of CK2β is well ordered and contains two non-canonical zinc finger loops termed “knuckles” (Cys-X4-Cys and Cys-X2-Cys) contained in the invariant motif CPX3C-X22-CPXC. The two knuckles are placed at almost 90° to each other, resulting in tetrahedral geometry of zinc ion. Based on pronounced structural similarity and residual sequence similarity, the zinc binding motif present in CK2β belongs to the sub-family of zinc ribbon domains. This motif resembles the Zn-ribbon structure of transcription factors TFIIS,25 TFIIB,26 the RNA polymerase II subunit 9 RPB9,27 and Topoisomerase I and III28 (fig. 3). Interestingly, the three β strands and the P loop that form the core of the Zn2+ binding motif of CK2β show a striking similar topology to the structure depicted for TFIIS (fig. 4). The knuckles of the Zn2+ binding site of CK2β are similar to those described for TFIIS and overall, the zinc ribbon motif of CK2β aligns structurally with an RMSD of 1.13 Å (96 atoms) with TFIIS. The β sheet surface of the Zn ribbon motif in CK2β is remarkable for its hydrophobicity, with 13 hydrophobic side chains defining the central surface. Unlike TFIIS which is a highly soluble nucleic-acid binding domain, the zinc ribbon motif of CK2β makes many hydrophobic interactions with the zinc ribbon motif of the other monomer forming the protein-protein interface. Most of the interactions between two CK2β monomers are contacts between residues that are localized at the edge of the Cys109-X4-Cys114 element and on the β3 strand. In this core region, several conserved hydrophobic residues make van der Waals interactions that form several important contacts between the two monomers (fig. 5). The most significant contacts are Pro 110, Tyr 144, and Lys 147 of one monomer which make hydrophobic contacts with their counterpart residues on the other monomer. Away from the two-fold axis, important hydrophobic interactions can be found such as Val A 112 with Val B 143 and Leu B 124. The Cys109-X4-Cys114 element and the β3 strand form a continuous interface that buries a total area of 540 Å2 for each monomer and defines the interface between two CK2β molecules (fig. 6). In contrast, the unvariant region located between the β1 and β2 sheets of the zinc finger motif (Gly123-Ileu 127) is not involved in the formation of the interface between two CK2β monomers. The conformationally prominent residues in this region extend onto the molecular surface of the CK2β homodimer generating potential sites of interaction with other molecules.

Figure 3. Structure-based sequence alignement of zinc ribbon domains in representative CK2β proteins and in members of the topoisomerase family.

Figure 3

Structure-based sequence alignement of zinc ribbon domains in representative CK2β proteins and in members of the topoisomerase family. 1. Protein name : CK2β, CK2β regulatory subunit ; RPB9, DNA-directed RNA polymerase II subunit (more...)

Figure 4. Ribbon representations of the zinc ribbon domains of CK2β and of transcription elongation factor TFIIS.

Figure 4

Ribbon representations of the zinc ribbon domains of CK2β and of transcription elongation factor TFIIS. The β strands are shown as pink arrows, loops as brown lines and zinc as blue sphere. (adapted from ref. ).

Figure 5. Ribbon representation of the dimer interface.

Figure 5

Ribbon representation of the dimer interface. The β strands are shown as pink arrows,loops as brown lines and zinc as a blue sphere. Amino acid chains and the water molecule involved in the protein-protein interaction, and the zinc ligands are (more...)

Figure 6. Worm representation of the CK2β dimer with the contact interface between monomers.

Figure 6

Worm representation of the CK2β dimer with the contact interface between monomers. The surface is color coded according to the difference between the distance and sum of van der Waals radii of the two atoms forming the interface. The distance (more...)

Implications for CK2 Functions

The regulatory CK2β subunit alone has no known catalytic activity, but it does associate with the catalytic CK2a subunit to generate a stable holoenzyme complex. Several studies suggest that the regulatory subunit modulates the ability of CK2a to interact with and to phosphorylate substrate proteins.29-31 Thus, CK2β appears as a crucial mediator of cellular functions of CK2. Furthermore, CK2β has been reported to be an interacting partner and activator of the mammalian A-Raf kinase21 and an inhibitor of the Xenopus laevis c-Mos serine/threonine kinase.32 In addition, the CK2β3 isoform present in Arabidopsis thaliana has been identified as an interacting partner of the circadian clock-associated 1 protein and interferes with regulation of circadian rhythms upon overexpression.33 Taking together, these observations suggest a regulatory function for CK2β in signaling networks.

It has been demonstrated that in living cells, the CK2β subunit is synthetized in excess of CK2α and interacts slowly with it.34 Therefore a vast majority of CK2α can potentially interact with CK2β. The β-β dimerization which can occurs in the absence of CK2α is a prerequisite for the incorporation of catalytic CK2 subunits into tetrameric complexes.35 The high-resolution structure of the human CK2 holoenzyme (fig. 7) revealed that the CK2β homodimer is the building block of this molecular hetero-complex bridging the two catalytic subunits 36. Modification of sulfhydryl groups of all cysteinyl residues of recombinant CK2β using p-chloromercuribenzoid acid abrogated the ability of the protein to form either homodimer or canonical α2β2 heterotetramers.37 A more direct approach to study the functional significance of the zinc ribbon motif of CK2β used CK2β mutants in which Cys 109 and Cys 114 were exchanged to serines.38 As expected, these mutations disrupted the zinc binding motif and resulted in loss of interactions between CK2β subunits. Interestingly, these mutants also failed to interact with catalytic CK2 subunits. The high-resolution structure of tetrameric CK2 (fig. 7) also shows how stable binding of the catalytic subunits requires interactions with both C-terminal tails of the CK2β dimer in a manner such that dimerization-deficient CK2β mutants are not able to interact with CK2α.36 The importance of CK2β dimerization for the in vivo CK2β functions was demonstrated in D. melanogaster by expression of mutagenised DmCK2β transgenes in a DmCK2β null mutant background.18 Mutations of either cysteinyl residue pair (109/114 or 137/140) involved in Zn2+ binding resulted in a CK2β protein which was unable to rescue the lethality of the CK2β null mutant. The failure of these mutants to substitute for the loss of endogenous DmCK2β function could be due to misregulation of the catalytic CK2 subunit, a loss of interaction with a critical CK2β binding partner or an accelerated protein turnover of the mutated proteins.38 Importantly, these studies emphasize the absolute requirement of the β-β dimerisation motif for CK2β function.

Figure 7. Overall shape of the human CK2 holoenzyme showing that the CK2β homodimer is the building block of this hetero-complex, bridging the two catalytic subunits.

Figure 7

Overall shape of the human CK2 holoenzyme showing that the CK2β homodimer is the building block of this hetero-complex, bridging the two catalytic subunits. The view is perpendicular to the C2 axis. The two CK2β chains are drawn in blue (more...)

The regulatory CK2β subunit has been shown to exert control over the catalytic activity of CK2 at a number of possible levels, i.e., in enhancing the catalytic activity and stability of CK2, and in the modulation of its substrate selectivity. The contribution of the CK2β subunit to the catalytic activity of CK2a was evaluated comparing the phosphorylation in vitro of different CK2 substrates by the isolated CK2a subunit or the tetrameric holoenzyme. 39 It was observed that CK2β modulates the ability of the catalytic CK2α subunit to interact with and phosphorylate substrate proteins demonstrating that CK2β plays a key role in the targeting of CK2 substrates. We have extended this study, analyzing the contribution of the zinc ribbon motif of CK2β in the regulation of the substrate specificity of catalytic CK2α subunit. CK2β mutants were constructed in which two of the conserved zinc ribbon residues, Pro110 and Val143, located at the edge of the Cys109-X4-Cys114 element and on the β3 strand respectively, were mutated to aspartic acid (fig. 5). Reconstitution experiments showed that the recombinant mutant proteins behave as wild type CK2β to form homodimers (fig. 8A). They were also fully competent to interact with the catalytic subunits of CK2 to generate the canonical multi-subunit holoenzyme (fig. 8B). Polyamine binding activity of the mutant CK2β proteins were also unchanged (not shown). Unexpectedly, we observed that the substrate specificity of the reconstituted mutant holoenzymes was very similar to the one observed for the isolated CK2α catalytic subunit indicating that both mutants were defective in regulating the associated catalytic CK2a subunit (fig. 9). Overall, these results show that the zinc ribbon mutants are fully competent to reconstitute an apparently normal tetrameric CK2. However, the enzymatic activity of the reconstituted CK2 holoenzyme complex was severely affected by the mutations in the zinc ribbon motif.

Figure 8. Biochemical characterization of mutant CK2β subunits.

Figure 8

Biochemical characterization of mutant CK2β subunits. A) Gel exclusion chromatography of wt CK2β and mutants CK2βP110D and CK2β>V143D. Proteins were chromatographed on a Ultrogel ACA44 column equilibrated in 20mM (more...)

Figure 9. Stimulation of CK2α subunit catalytic activity by wt and mutated CK2β subunits.

Figure 9

Stimulation of CK2α subunit catalytic activity by wt and mutated CK2β subunits. Known CK2 protein substrates (Topoisomerase II, Engrailed, PHAX) were phosphorylated by CK2α in the presence of increasing amount of wt CK2β (more...)

Based on our results, we postulate that mutations in this domain of residues that form important contacts between the CK2β monomers would induce conformational changes that alleviate the regulatory function of this subunit on CK2 activity. Collectively, these studies show the functional importance of the zinc ribbon motif of CK2β. A correct relative positioning of the sites of contact between the two CK2β monomers is likely to be important for forming a functional CK2β homodimer. The loss of function for the corresponding CK2β mutants suggests that even though Pro110 and Val143 residues play no direct role in catalysis, the structural integrity of the β-β protein interface is important for the regulation of the CK2 catalytic activity.

Beside the complex nature of the interaction between the catalytic and regulatory subunits of CK2, there is a growing body of evidence to suggest that CK2β also performs functions that are distinct from its role as a regulatory subunit of CK2 and the notion that the catalytic subunits of CK2 exist outside the holoenzyme complex was brought by several studies. In this respect, the crystal structure of tetrameric CK2 highlighted that the limited surface of the α-β contacts suggests an inter-subunit flexibility compatible with an association-dissociation in vivo.36 In addition, recent evidence from live-cell fluorescence imaging have revealed the independent movements of the catalyic and regulatory CK2 subunits within cells.40 It was observed in this study, that both CK2 subunits were separately translocated into the nucleus of growing cells and that CK2β was not targeted to the nucleus by virtue of its stable association with CK2α. In contrast, a deletion mutant unable to interact with CK2α but containing the zinc ribbon motif was efficiently targeted to the nucleus (fig. 10). Interestingly, GFP-CK2β mutant in which Cys109 and Cys114 were replaced by serine residues, did not accumulate within the nucleus but remained in the cytoplasm (fig. 10). These observations suggest that the integrity of the zinc ribbon motif, which is pivotal in the CK2β homodimer structure, is also instrumental for the correct nuclear targeting of the CK2β subunit in living cells.

Figure 10. Nuclear import of mutant CK2β subunits.

Figure 10

Nuclear import of mutant CK2β subunits. NIH3T3 cells were transiently transfected with different GFP-CK2β constructs as illustrated in the diagram. Transfected cells were observed for protein localization. (adapted from ref. ).


As a result of the structural work highlighted here and other biochemical studies, we have now dramatically improved our evaluation of the structural conformation of the isolated CK2 subunits and their arrangement within tetrameric complexes.19,36,41 The structure of the CK2β homodimer revealed the presence of a zinc binding motif mediating the dimerization of the protein. Thus, the regulatory subunit of CK2 joins the expanding subset of self-associating zinc ribbon proteins in which the Zn binding motif mediates protein-protein interactions. The zinc ribbons which are the largest fold group of zinc fingers frequently display limited sequence and structural similarity, mainly restricted to the zinc ligands and the zinc knuckle motifs. However, the zinc binding motif of CK2β shows a clear structural similarity with the zinc binding sites found in representative members of the classical zinc ribbon fold group such as the transcription factors TFIIS, TFIIB, RPB9 and Topoisomerase I and III. In the case of CK2β, the zinc ribbon motif has been now recognized as an important structural feature of this regulatory protein. The integrity of this motif appears crucial not only for the correct molecular architecture of this important protein, but also for its regulatory functions.


We acknowledge L. Chantalat and O. Dideberg for help in generating structural diagrams. We thank A. Larsen for providing us with Topoisomerase II, A. Joliot for Engrailed, and C. Mazza for the PHAX protein. Work on CK2 in our group is supported by grants from the INSERM, the CNRS (contrat 8BC06G), the Commissariat à l'Energie Atomique, the Association pour la Recherche contre le Cancer (réseau ARECA), and the Ligue Nationale contre le Cancer.


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