4pds | pdb_00004pds
Crystal structure of Rad53 kinase domain and SCD2 in complex with AMPPNP
Structural highlights
FunctionRAD53_YEAST Controls S-phase checkpoint as well as G1 and G2 DNA damage checkpoints. Phosphorylates proteins on serine, threonine, and tyrosine. Prevents entry into anaphase and mitotic exit after DNA damage via regulation of the Polo kinase CDC5. Seems to be involved in the phosphorylation of RPH1.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe protein kinase Rad53 is a key regulator of the DNA damage checkpoint in budding yeast. Its human ortholog, CHEK2, is mutated in familial breast cancer and mediates apoptosis in response to genotoxic stress. Autophosphorylation of Rad53 at residue Thr354 located in the kinase activation segment is essential for Rad53 activation. In this study, we assessed the requirement of kinase domain dimerization and the exchange of its activation segment during the Rad53 activation process. We solved the crystal structure of Rad53 in its dimeric form and found that disruption of the observed head-to-tail, face-to-face dimer structure decreased Rad53 autophosphorylation on Thr354 in vitro and impaired Rad53 function in vivo. Moreover, we provide critical functional evidence that Rad53 trans-autophosphorylation may involve the interkinase domain exchange of helix alphaEF via an invariant salt bridge. These findings suggest a mechanism of autophosphorylation that may be broadly applicable to other protein kinases. Structural basis of Rad53 kinase activation by dimerization and activation segment exchange.,Wybenga-Groot LE, Ho CS, Sweeney FD, Ceccarelli DF, Jane McGlade C, Durocher D, Sicheri F Cell Signal. 2014 May 9. pii: S0898-6568(14)00174-0. doi:, 10.1016/j.cellsig.2014.05.004. PMID:24815189[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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