Journal
STRUCTURE
Volume 29, Issue 6, Pages 531-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2021.03.007
Keywords
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Funding
- Cancer Research UK [C302/A14532, C302/A24386]
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CHK1 is a protein kinase that phosphorylates multiple targets downstream of activated ATR, and its interaction with CLASPIN is essential for its activation by ATR. The crystal structure of CHK1 bound to a high-affinity motif from CLASPIN reveals the mechanism of how CLASPIN functions as a scaffold for CHK1 activation.
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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