Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange.
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.
Mesh Terms:
Adenosine Diphosphate, Azepines, Catalytic Domain, Cell Cycle Proteins, DNA Damage, DNA-Binding Proteins, Dimerization, Enzyme Activation, Humans, Models, Molecular, Phosphorylation, Protein Conformation, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Pyrroles, Signal Transduction, Trans-Activators, Tumor Suppressor Proteins
Adenosine Diphosphate, Azepines, Catalytic Domain, Cell Cycle Proteins, DNA Damage, DNA-Binding Proteins, Dimerization, Enzyme Activation, Humans, Models, Molecular, Phosphorylation, Protein Conformation, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Pyrroles, Signal Transduction, Trans-Activators, Tumor Suppressor Proteins
EMBO J.
Date: Jul. 12, 2006
PubMed ID: 16794575
View in: Pubmed Google Scholar
Download Curated Data For This Publication
152576
Switch View:
- Interactions 2