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

Autor: Michelle D. Garrett, Laurence H. Pearl, K. Boxall, Angela Paul, Antony W. Oliver, S. Elaine Barrie, G. Wynne Aherne, Sibylle Mittnacht
Rok vydání: 2006
Předmět:
Models
Molecular
animal structures
Protein Conformation
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
Mitogen-activated protein kinase kinase
Protein Serine-Threonine Kinases
environment and public health
General Biochemistry
Genetics and Molecular Biology
Article
MAP2K7
Catalytic Domain
Humans
ASK1
Pyrroles
Phosphorylation
Molecular Biology
Checkpoint Kinase 2
General Immunology and Microbiology
biology
MAP kinase kinase kinase
General Neuroscience
Cyclin-dependent kinase 5
Tumor Suppressor Proteins
Cyclin-dependent kinase 2
Azepines
Cell biology
Protein Structure
Tertiary
Adenosine Diphosphate
DNA-Binding Proteins
Enzyme Activation
enzymes and coenzymes (carbohydrates)
Biochemistry
biology.protein
Trans-Activators
Cyclin-dependent kinase 9
biological phenomena
cell phenomena
and immunity
Dimerization
DNA Damage
Signal Transduction
Zdroj: The EMBO journal. 25(13)
ISSN: 0261-4189
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: