Day, Matthew, Parry-Morris, Sarah, Houghton-Gisby, Jack, Oliver, Antony W and Pearl, Laurence H (2021) Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold protein. Structure, 29 (6). 531-539.e3. ISSN 0969-2126

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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.

Item Type:	Article
Keywords:	DNA damage signaling, checkpoints, protein kinase mechanisms
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor:	Mx Elements Account
Depositing User:	Mx Elements Account
Date Deposited:	24 Sep 2021 11:22
Last Modified:	30 Nov 2021 16:17
URI:	http://sro.sussex.ac.uk/id/eprint/101890

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