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bioRxiv · 10.1101/2020.10.02.323733

Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold protein

Day, M.·Parry-Morris, S. L.·Houghton-Gisby, J.·Oliver, A. W.·Pearl, L. H.
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Abstract

CHK1 is a protein kinase that functions downstream of activated ATR to phosphorylate multiple targets as part of intra-S and G2/M DNA damage checkpoints. Its role in allowing cells to survive replicative stress has made it an important target for anti-cancer drug discovery. Activation of CHK1 by ATR depends on their mutual interaction with CLASPIN - a natively unstructured protein that interacts with CHK1 through a cluster of phosphorylation sites in its C-terminal half. We have now determined the crystal structure of the kinase domain of CHK1 bound to a high-affinity motif from CLASPIN. Our data show that CLASPIN engages a conserved site on CHK1 adjacent to the substrate-binding cleft, involved in phosphate sensing in other kinases. The CLASPIN motif is not phosphorylated by CHK1, nor does it affect phosphorylation of a CDC25 substrate peptide, suggesting that it functions purely as a scaffold for CHK1 activation by ATR.

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Day, M., Parry-Morris, S. L., Houghton-Gisby, J., Oliver, A. W., Pearl, L. H.. 2020-10-02. Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold protein. https://doi.org/10.1101/2020.10.02.323733

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