Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs.

Centro de Investigaciones Biologicas (CIB), Spanish National Research Council (CSIC), Ramiro de Maeztu 9, Campus Complutense University, Madrid 28040, Spain.
Recognition of DNA double-strand breaks during non-homologous end joining is carried out by the Ku70-Ku80 protein, a 150 kDa heterodimer that recruits the DNA repair kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to the lesion. The atomic structure of a truncated Ku70-Ku80 was determined; however, the subunit-specific carboxy-terminal domain of Ku80--essential for binding to DNA-PKcs--was determined only in isolation, and the C-terminal domain of Ku70 was not resolved in its DNA-bound conformation. Both regions are conserved and mediate protein-protein interactions specific to mammals. Here, we reconstruct the three-dimensional structure of the human full-length Ku70-Ku80 dimer at 25 A resolution, alone and in complex with DNA, by using single-particle electron microscopy. We map the C-terminal regions of both subunits, and their conformational changes after DNA and DNA-PKcs binding to define a molecular model of the functions of these domains during DNA repair in the context of full-length Ku70-Ku80 protein.
Mesh Terms:
Antigens, Nuclear, DNA, DNA-Activated Protein Kinase, DNA-Binding Proteins, Dimerization, Humans, Microscopy, Electron, Protein Conformation, Protein Interaction Mapping
EMBO Rep. Jan. 01, 2007; 8(1);56-62 [PUBMED:17159921]
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