Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange

Oliver, Antony W, Paul, Angela, Boxall, Katherine J, Barrie, S Elaine, Aherne, G Wynne, Garrett, Michelle D, Mittnacht, Sibylle and Pearl, Laurence H (2006) Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. EMBO Journal, 25 (13). pp. 3179-3190. ISSN 0261-4189

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Abstract

The protein kinase Chk2 (checkpoint kinase 2) is a major effector of the replication checkpoint. Chk2 activation is initiated by phosphorylation of Thr68, in the serine-glutamine/threonine-glutamine cluster domain (SCD), by ATM. The phosphorylated SCD-segment binds to the FHA domain of a second Chk2 molecule, promoting dimerisation of the protein and triggering phosphorylation of the activation segment/T-loop in the kinase domain. We have now determined the structure of the kinase domain of human Chk2 in complexes with ADP and a small-molecule inhibitor debromohymenialdisine. The structure reveals a remarkable dimeric arrangement in which T-loops are exchanged between protomers, to form an active kinase conformation in trans. Biochemical data suggest that this dimer is the biologically active state promoted by ATM-phosphorylation, and also suggests a mechanism for dimerisation-driven activation of Chk2 by trans-phosphorylation.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
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Depositing User: Antony Oliver
Date Deposited: 06 Feb 2012 19:56
Last Modified: 14 Jun 2012 08:34
URI: http://sro.sussex.ac.uk/id/eprint/23111
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