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

DOI: 10.1016/j.str.2021.03.007 DOI Help

Authors: Matthew Day (University of Sussex) , Sarah Parry-Morris (University of Sussex) , Jack Houghton-Gisby (University of Sussex) , Antony W. Oliver (University of Sussex) , Laurence H. Pearl (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 277

State: Published (Approved)
Published: March 2021

Open Access Open Access

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.

Journal Keywords: DNA damage signaling; protein kinase mechanisms; checkpoints

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 07/04/2021 11:53

Documents:
1-s2.0-S0969212621000800-main.pdf

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)