title: The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair.
abstract: The MR (Mre11 nuclease and Rad50 ABC ATPase) complex is an evolutionarily conserved sensor for DNA double-strand breaks, highly genotoxic lesions linked to cancer development. MR can recognize and process DNA ends even if they are blocked and misfolded. To reveal its mechanism, we determined the crystal structure of the catalytic head of Thermotoga maritima MR and analyzed ATP-dependent conformational changes. MR adopts an open form with a central Mre11 nuclease dimer and two peripheral Rad50 molecules, a form suited for sensing obstructed breaks. The Mre11 C-terminal helix-loop-helix domain binds Rad50 and attaches flexibly to the nuclease domain, enabling large conformational changes. ATP binding to the two Rad50 subunits induces a rotation of the Mre11 helix-loop-helix and Rad50 coiled-coil domains, creating a clamp conformation with increased DNA-binding activity. The results suggest that MR is an ATP-controlled transient molecular clamp at DNA double-strand breaks.
authors: Center for Integrated Protein Science Munich, Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
authors: Katja
authors: K
authors: Lammens
authors: Derk J
authors: DJ
authors: Bemeleit
authors: Carolin
authors: C
authors: Möckel
authors: Emanuel
authors: E
authors: Clausing
authors: Alexandra
authors: A
authors: Schele
authors: Sophia
authors: S
authors: Hartung
authors: Christian B
authors: CB
authors: Schiller
authors: Maria
authors: M
authors: Lucas
authors: Christof
authors: C
authors: Angermüller
authors: Johannes
authors: J
authors: Söding
authors: Katja
authors: K
authors: Strässer
authors: Karl-Peter
authors: KP
authors: Hopfner
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D012441:Saccharomyces cerevisiae / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D053838:Scattering, Small Angle; D020124:Thermotoga maritima / Q000737:chemistry* / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C086930:RAD50 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae; D045643:DNA Repair Enzymes