Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 28, Pages 7367-7372Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1707386114
Keywords
DNA repair; V(D)J recombination; NHEJ; cryo-EM; structure
Categories
Funding
- National Institutes of Health [AI125535]
- Intel academic grant
- Thousand-Talent Plan of China
- NIH, Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID) [AI100645]
- National Science Foundation [ECS-0335765]
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DNA-dependent protein kinase (DNA-PK) is a large protein complex central to the nonhomologous end joining (NHEJ) DNA-repair pathway. It comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer of DNA-binding proteins Ku70 and Ku80. Here, we report the cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs at 4.4-angstrom resolution and the DNA-PK holoenzyme at 5.8-angstrom resolution. The DNA-PKcs structure contains three distinct segments: the N-terminal region with an arm and a bridge, the circular cradle, and the head that includes the kinase domain. Two perpendicular apertures exist in the structure, which are sufficiently large for the passage of dsDNA. The DNA-PK holoenzyme cryo-EM map reveals density for the C-terminal globular domain of Ku80 that interacts with the arm of DNA-PKcs. The Ku80-binding site is adjacent to the previously identified density for the DNA-binding region of the Ku70/Ku80 complex, suggesting concerted DNA interaction by DNA-PKcs and the Ku complex.
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