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EMBO J. 2006 Jul 12;25(13):3179-90. Epub 2006 Jun 22.

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

Author information

1
Section of Structural Biology, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, Chelsea, London, UK. antony.oliver@icr.ac.uk

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.

PMID:
16794575
PMCID:
PMC1500991
DOI:
10.1038/sj.emboj.7601209
[Indexed for MEDLINE]
Free PMC Article

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