Human Cdc-like Kinase

The Clk family consists of four kinases that display so-called dual specificity,
i.e., they are capable of phosphorylating both Ser/Thr as well as Tyr residues.

CLK homologues have been isolated from a number of organisms including Arabidopsis,
Drosophila, mouse and human.
The kinase domain of CLK family members is located at the C terminus
and contains the family signature motif ‘EHLAMMERILG’,
giving rise to the name of these kinases: ‘LAMMER’ kinases.
Mutations in the Drosophila CLK homologue,
darkener of apricot (DOA) suggest that CLK family members
play an important role during development.
Mutations in DOA are embryonic lethal and lead to defects in differentiation,
including abnormalities in segmentation, eye formation, and neuronal development.

CLK1 also plays an important role regulating RNA splicing.
It has been shown that CLK1 forms complexes with and phosphorylates members
of the SR family of splicing factors.
Overexpression affects splicing site selection of pre-mRNA
of both its own transcript and adenovirus E1A transcripts
in vivo which led to the current model that Clk family members
regulate alternative splicing by phosphorylation of SR proteins.
In addition, overexpression of catalytically inactive CLK1 localize
to nuclear speckles where splicing factors are concentrated,
whereas the wild-type enzymes distribute throughout the nucleus and cause speckles to dissolve.

We solved the structure of human CLK1 kinase domain at 1.7 Ã… resolution
in complex with the marine sponge metabolite hymenialdisine
which has been shown to be a potent ATP-competitive inhibitor of MEK-1,
Cdk’s, GSK-3b and CK1.
Hymenialdisine also inhibits G2 phase DNA damage checkpoint
and blocks IL-8 production in U937 cells by inhibiting the activation of NF-kB.
Hymenialdisine is therefore a potential therapeutic reagent for the treatment
of diabetes and neurodegenerative disorders.