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

By Antony W Oliver, Angela Paul, Katherine J Boxall, S Elaine Barrie, G Wynne Aherne, Michelle D Garrett, Sibylle Mittnacht and Laurence H Pearl

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

Publisher: Nature Publishing Group
Year: 2006
OAI identifier: oai:sro.sussex.ac.uk:23111
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