title: Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange.
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.
authors.affiliation: Section of Structural Biology, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, Chelsea, London, UK. antony.oliver@icr.ac.uk
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.forename: Angela
authors.initials: A
authors.lastname: Paul
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Boxall
authors.forename: S Elaine
authors.initials: SE
authors.lastname: Barrie
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: Sibylle
authors.initials: S
authors.lastname: Mittnacht
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D064007:Ataxia Telangiectasia Mutated Proteins; D001381:Azepines / Q000737:chemistry; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000737:chemistry; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry; D015398:Signal Transduction; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000737:chemistry
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011758:Pyrroles; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C097660:debromohymenialdisine; D000244:Adenosine Diphosphate; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases