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PMID: 21937514 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ATP driven structural changes of the bacterial Mre11:Rad50 catalytic head complex.

Nucleic acids research ·Vol. 40 ·No. 2 ·2012-01-00 ·Pages 914-27

Möckel C, Lammens K, Schele A, Hopfner KP

Abstract

DNA double-strand breaks (DSBs) threaten genome stability in all kingdoms of life and are linked to cancerogenic chromosome aberrations in humans. The Mre11:Rad50 (MR) complex is an evolutionarily conserved complex of two Rad50 ATPases and a dimer of the Mre11 nuclease that senses and processes DSBs and tethers DNA for repair. ATP binding and hydrolysis by Rad50 is functionally coupled to DNA-binding and tethering, but also regulates Mre11's nuclease in processing DNA ends. To understand how ATP controls the interaction between Mre11 and Rad50, we determined the crystal structure of Thermotoga maritima (Tm) MR trapped in an ATP/ADP state. ATP binding to Rad50 induces a large structural change from an open form with accessible Mre11 nuclease sites into a closed form. Remarkably, the NBD dimer binds in the Mre11 DNA-binding cleft blocking Mre11's dsDNA-binding sites. An accompanying large swivel of the Rad50 coiled coil domains appears to prepare the coiled coils for DNA tethering. DNA-binding studies show that within the complex, Rad50 likely forms a dsDNA-binding site in response to ATP, while the Mre11 nuclease module retains a ssDNA-binding site. Our results suggest a possible mechanism for ATP-dependent DNA tethering and DSB processing by MR.

MeSH Terms
Adenosine Diphosphate/chemistry,metabolism Adenosine Triphosphatases/chemistry,metabolism Adenosine Triphosphate/chemistry,metabolism Bacterial Proteins/chemistry,metabolism DNA/metabolism Endodeoxyribonucleases/chemistry,metabolism Exodeoxyribonucleases/chemistry,metabolism Models, Molecular Protein Binding Protein Conformation Thermotoga maritima
Chemicals
Bacterial Proteins Adenosine Diphosphate Adenosine Triphosphate DNA Endodeoxyribonucleases Exodeoxyribonucleases Adenosine Triphosphatases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Möckel Carolin
Gene Center and Department of Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 25, 81377, Munich, Germany.
Lammens Katja
Schele Alexandra
Hopfner Karl-Peter
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkr749
Published
2012-01-00
Epub
2011-00-21
Pages
914-27
Language
English
Region
England
NLM ID
0411011
PMCID
PMC3258140
Subset
IM
Grants
NIAID NIH HHS · U19AI83025 · United States
Databases
PDB
3THO
External Links
PubMed source DOI: 10.1093/nar/gkr749 PMC Full Text View journal details
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