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  • The EMBO Journal (2006) 25, 3179 - 3190
  • doi:10.1038/sj.emboj.7601209

Published online: 22 June 2006

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

Antony W Oliver1, Angela Paul2, Katherine J Boxall3, S Elaine Barrie3, G Wynne Aherne3, Michelle D Garrett3, Sibylle Mittnacht2 and Laurence H Pearl1

  1. Cancer Research UK DNA Repair Enzymes Group, Section of Structural Biology, The Institute of Cancer Research, Chelsea, London, UK
  2. Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, Chelsea, London, UK
  3. Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK

Correspondence to:

Antony W Oliver, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, 237 Fulham Road, Chelsea, London SW3 6JB, UK. Tel.: +44 20 7153 5571; Fax: +44 20 6153 5457; E-mail: antony.oliver@icr.ac.uk

Laurence H Pearl, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, 237 Fulham Road, Chelsea, London SW3 6JB, UK. Tel.: +44 20 7153 5571; Fax: +44 20 6153 5457; E-mail: laurence.pearl@icr.ac.uk

Received 8 February 2006; Accepted 31 May 2006

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.

  • Keywords:

    • cancer,
    • CHEK2,
    • CHK2,
    • inhibitor,
    • kinase