title: ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair.
abstract: The Rad50 ABC-ATPase complex with Mre11 nuclease is essential for dsDNA break repair, telomere maintenance and ataxia telangiectasia-mutated kinase checkpoint signaling. How Rad50 affects Mre11 functions and how ABC-ATPases communicate nucleotide binding and ligand states across long distances and among protein partners are questions that have remained obscure. Here, structures of Mre11-Rad50 complexes define the Mre11 2-helix Rad50 binding domain (RBD) that forms a four-helix interface with Rad50 coiled coils adjoining the ATPase core. Newly identified effector and basic-switch helix motifs extend the ABC-ATPase signature motif to link ATP-driven Rad50 movements to coiled coils binding Mre11, implying an ~30-Å pull on the linker to the nuclease domain. Both RBD and basic-switch mutations cause clastogen sensitivity. Our new results characterize flexible ATP-dependent Mre11 regulation, defects in cancer-linked RBD mutations, conserved superfamily basic switches and motifs effecting ATP-driven conformational change, and they provide a unified comprehension of ABC-ATPase activities.
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors: Gareth J
authors: GJ
authors: Williams
authors: R Scott
authors: RS
authors: Williams
authors: Jessica S
authors: JS
authors: Williams
authors: Gabriel
authors: G
authors: Moncalian
authors: Andrew S
authors: AS
authors: Arvai
authors: Oliver
authors: O
authors: Limbo
authors: Grant
authors: G
authors: Guenther
authors: Soumita
authors: S
authors: SilDas
authors: Michal
authors: M
authors: Hammel
authors: Paul
authors: P
authors: Russell
authors: John A
authors: JA
authors: Tainer
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000595:Amino Acid Sequence; D019843:Archaeal Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D004260:DNA Repair; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D019843:Archaeal Proteins; C480032:Rad50 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C415985:Mre11 protein, archaeal; C415984:Rad50 protein, archaeal; D000251:Adenosine Triphosphatases