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

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.

SUBMITTER: Day M

PROVIDER: S-EPMC8204404 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Day Matthew M Parry-Morris Sarah S Houghton-Gisby Jack J Oliver Antony W AW Pearl Laurence H LH

Structure (London, England : 1993) 20210330 6

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 th ...[more]

PMID: 33789090

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