Crystal structure of the Mre11-Rad50-ATPγS complex: understanding the interplay between Mre11 and Rad50

Communication between Mre11 and Rad50 in the MR complex is critical for the sensing, damage signaling, and repair of DNA double-strand breaks. To understand the basis for interregulation between Mre11 and Rad50, we determined the crystal structure of the Mre11-Rad50-ATPγS complex. Mre11 brings the t...

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Bibliographic Details
Published in:Genes & development 2011-05, Vol.25 (10), p.1091-1104
Main Authors: Lim, Hye Seong, Kim, Jin Seok, Park, Young Bong, Gwon, Gwang Hyeon, Cho, Yunje
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - analogs & derivatives
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - metabolism
Amino Acid Motifs
Archaeal Proteins - chemistry
Archaeal Proteins - metabolism
Binding Sites
Endodeoxyribonucleases - chemistry
Endodeoxyribonucleases - metabolism
Exodeoxyribonucleases - chemistry
Exodeoxyribonucleases - metabolism
Gene Expression Regulation, Archaeal
Hydrolysis
Methanococcus - chemistry
Methanococcus - enzymology
Methanococcus - genetics
Methanococcus - metabolism
Models, Molecular
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
Research Paper
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Summary:Communication between Mre11 and Rad50 in the MR complex is critical for the sensing, damage signaling, and repair of DNA double-strand breaks. To understand the basis for interregulation between Mre11 and Rad50, we determined the crystal structure of the Mre11-Rad50-ATPγS complex. Mre11 brings the two Rad50 molecules into close proximity and promotes ATPase activity by (1) holding the coiled-coil arm of Rad50 through its C-terminal domain, (2) stabilizing the signature motif and P loop of Rad50 via its capping domain, and (3) forming a dimer through the nuclease domain. ATP-bound Rad50 negatively regulates the nuclease activity of Mre11 by blocking the active site of Mre11. Hydrolysis of ATP disengages Rad50 molecules, and, concomitantly, the flexible linker that connects the C-terminal domain and the capping domain of Mre11 undergoes substantial conformational change to relocate Rad50 and unmask the active site of Mre11. Our structural and biochemical data provide insights into understanding the interplay between Mre11 and Rad50 to facilitate efficient DNA damage repair.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.2037811