Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The EMBO journal, 2006-07, Vol.25 (13), p.3179-3190

Ort / Verlag

Chichester, UK: John Wiley & Sons, Ltd

Erscheinungsjahr

2006

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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.