Allosteric effects mediate CHK2 phosphorylation of the p53 transactivation domain

Craig, A., Scott, M. , Burch, L., Smith, G., Ball, K. and Hupp, T. (2003) Allosteric effects mediate CHK2 phosphorylation of the p53 transactivation domain. EMBO Reports, 4(8), pp. 787-792. (doi:10.1038/sj.embor.embor901) (PMID:12897801) (PMCID:PMC1326341)

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Abstract

The tumour suppressor p53 is a tetrameric protein that is phosphorylated in its BOX‐I transactivation domain by checkpoint kinase 2 (CHK2) in response to DNA damage. CHK2 cannot phosphorylate small peptide fragments of p53 containing the BOX‐I motif, indicating that undefined determinants in the p53 tetramer mediate CHK2 recognition. Two peptides derived from the DNA‐binding domain of p53 bind to CHK2 and stimulate phosphorylation of full‐length p53 at Thr 18 and Ser 20, thus identifying CHK2‐docking sites. CHK2 can be fully activated in trans by the two p53 DNA‐binding‐domain peptides, and can phosphorylate BOX‐I transactivation‐domain fragments of p53 at Thr 18 and Ser 20. Although CHK2 has a basal Ser 20 kinase activity that is predominantly activated towards Thr 18, CHK1 has constitutive Thr 18 kinase activity that is predominantly activated in trans towards Ser 20. Cell division cycle 25C (CDC25C) phosphorylation by CHK2 is unaffected by the p53 DNA‐binding‐domain peptides. The CHK2‐docking site in the BOX‐V motif is the smallest of the two CHK2 binding sites, and mutating certain amino acids in the BOX‐V peptide prevents CHK2 activation. A database search identified a p53 BOX‐I‐homology motif in p21WAF1 and although CHK2 is inactive towards this protein, the p53 DNA‐binding‐domain peptides induce phosphorylation of p21WAF1 at Ser 146. This provides evidence that CHK2 can be activated allosterically towards some substrates by a novel docking interaction, and identify a potential regulatory switch that may channel CHK2 into distinct signalling pathways in vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Scott, Dr Mary
Authors: Craig, A., Scott, M., Burch, L., Smith, G., Ball, K., and Hupp, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:EMBO Reports
Publisher:EMBO Press
ISSN:1469-221X
ISSN (Online):1469-3178

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