4PDP

Crystal structure of Rad53 kinase domain and SCD2

Summary for 4PDP

• Entry DOI: 10.2210/pdb4pdp/pdb
• Related: 4PDS
• Descriptor: Serine/threonine-protein kinase RAD53 (1 entity in total)
• Functional Keywords: ser/thr kinase domain, n-lobe, c-lobe, activation segment exchange, transferase
• Biological source: Saccharomyces cerevisiae (Baker's yeast)
• Total number of polymer chains: 2
• Total formula weight: 76853.33

Authors

Wybenga-Groot, L.E.,Ho, C.S.,Ceccarelli, D.F.,Sicheri, F. (deposition date: 2014-04-19, release date: 2014-05-28, Last modification date: 2023-09-27)

Primary citation

Wybenga-Groot, L.E.,Ho, C.S.,Sweeney, F.D.,Ceccarelli, D.F.,McGlade, C.J.,Durocher, D.,Sicheri, F.
Structural basis of Rad53 kinase activation by dimerization and activation segment exchange.
Cell Signal., 26:1825-1836, 2014

PubMed Abstract: The 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 αEF via an invariant salt bridge. These findings suggest a mechanism of autophosphorylation that may be broadly applicable to other protein kinases.

PubMed: 24815189
DOI: 10.1016/j.cellsig.2014.05.004

Experimental method

X-RAY DIFFRACTION (2.591 Å)