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Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold protein
journal contribution
posted on 2023-06-10, 01:08 authored by Matthew Day, Sarah Parry-Morris, Jack Houghton-Gisby, Antony OliverAntony Oliver, Laurence PearlLaurence PearlCHK1 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.
History
Publication status
- Published
File Version
- Published version
Journal
StructureISSN
0969-2126Publisher
ElsevierExternal DOI
Issue
6Volume
29Page range
531-539.e3Event location
United StatesDepartment affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-09-24First Open Access (FOA) Date
2021-09-24First Compliant Deposit (FCD) Date
2021-09-24Usage metrics
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