CSNK1G2: Human Casein Kinase I gamma-2 in complex with 5-Iodotubercidin
PDB Code: 2C47
CKI represents a unique group of serine/ threonine protein kinases that is ubiquitously expressed in eukaryotic organisms. Seven mammalian CKI isoforms (α, β, γ1, γ2, γ3, δ and ε) and various splice variants have been identified to date. CKI family members contain a highly conserved N-terminal catalytic domain coupled to a variable C-terminal region that ranges in size from 40 to 180 amino acids. Casein kinases have been described to act as monomeric, constitutively active enzymes.
The characterization of the substrate specificity of CKI isoforms initially led to the identification of the canonical consensus sequence S/T(P)-X1-2-S/T, indicating that modification of serine or threonine residues by CKI requires the preceding phosphorylation of amino acid residues N-terminal of the target site. This requirement of a priming phosphorylation by another kinase restricted CKI to a function in the hierarchical phosphorylation of substrates. However, further studies revealed that a cluster of acidic amino acids N-terminal of the target serine/ threonine and an acidic amino acid in position n-3 could substitute for the phosphoamino acid efficiently. This non-canonical motif consisting of the sequence SLS has been shown to be recognized by CKI in combination with a cluster of acidic amino acid residues C-terminal of the phosphoacceptor site. The CKI substrates NF-AT and β-catenin exhibit such motifs, but phosphorylation of this non-canonical motif is 15?25 fold less efficient compared to the motif primed by a phosphoamino acid.
Recently, it was shown that rat CKI-γ2 interacts with the adaptor protein NCK via a proline- rich sequence in rat CKI-γ2 called the PXXP motifs (VHPKVPSQPPHR), which are not present in either CKI-γ1 or CKI-γ3. This interaction contributes to the substrate specificity of CKI-γ2 bringing the kinase in close proximity with its downstream targets. For example it was shown that upon PDGF stimulation, CKI-γ2 phosphorylates the PDGF receptor which also associates with LCK, leading to receptor inactivation.
CKI-γ2 may affect the development of brain and has been associated with vesicular trafficking and neurotransmitter release from small synaptic vesicles. In addition, 10 single nucleotide polymorphisms (SNPs) have been identified and were linked to occurrence of febrile seizures during early childhood.
We structure determined CKI-γ2 in complex with Iodotubercidin (4-Amino-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine) which has been reported to be a potent and competitive inhibitor of the MAP kinase ERK2 (Ki = 530 nM). This compound has also been reported to inhibit adenosine kinase with a Ki of 30 nM.

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