Human SRPK2 (serine/arginine-rich protein-specific kinase 2) bound to purvalanol B

About this structure

The serine/arginine-rich protein-specific kinase 2, SRPK2, forms together with SRPK1 and SRPK3 a family of cell-cycle regulated Ser/Thr kinases. The substrates of SRPKs are splicing factors such as serine/arginine (SR) domain-containing proteins that are localized in nuclear speckles and mediate pre-mRNA splicing (Nakagawa et al., 2005). SRPKs are characterised by a bipartite kinase domain separated by a spacer region. The spacer region of SRPK2 comprises a proline rich region and a basic region which may act as nuclear localization signal, as well as an acidic domain, not present in SRPK1.

SRPK2 is highly expressed in brain as well as at a lower level in other organs (Wang et al., 1998). Although primarily located in the cytoplasm, SRPK2 can translocate to the nucleus, where it has been shown to be involved in regulation of cyclins (Jang et al., 2008) (Jang et al., 2009). In neurons ischemic conditions trigger phosphorylation of the SRPK2 residue Thr492 by AKT resulting in nuclear translocation, in cell cycle re-entry and neuronal apoptosis (Jang et al., 2009). In addition, knockdown experiments of SRPK2 in HeLa cells point to an essential role of SRPK2 for cell viability and splicosomal B complex formation (Mathew et al., 2008).

SRPK2 has been reported to phosphorylate the SR containing hepatitis B virus core protein, a prerequisite for pregenomic RNA encapsidation into viral capsids and thus presents a potential target for therapeutic intervention in HBV infection (Daub et al., 2002). High expression of SRPK2 has been found in some human AML patients and correlate with the oncogenic activity of cyclin A1 in leukemia and leukemia cell proliferation (Jang et al., 2008). Here we report the structure of the SRPK2 kinase domain at 2.5 Å resolution in complex with the ATP competitive inhibitor Purvalanol B.

References

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