Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA.
The human Rad50/Mre11/Nbs1 complex (hR/M/N) functions as an essential guardian of genome integrity by directing the proper processing of DNA ends, including DNA breaks. This biological function results from its ability to tether broken DNA molecules. hR/M/N's dynamic molecular architecture consists of a globular DNA-binding domain from which two 50-nm-long coiled coils protrude. The coiled coils are flexible and their apices can self-associate. The flexibility of the coiled coils allows their apices to adopt an orientation favourable for interaction. However, this also allows interaction between the tips of two coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Here we show that the dynamic architecture of hR/M/N is markedly affected by DNA binding. DNA binding by the hR/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favours intercomplex associations needed for DNA tethering. The hR/M/N complex thus is an example of a biological nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nm distant.
Moreno-Herrero
Fernando
F
Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands.
de Jager
Martijn
M
Dekker
Nynke H
NH
Kanaar
Roland
R
Wyman
Claire
C
Dekker
Cees
C
D017766:Acid Anhydride Hydrolases; D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D002021:Buffers; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D004247:DNA / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008024:Ligands; D000076228:MRE11 Homologue Protein; D018625:Microscopy, Atomic Force; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D009690:Nucleic Acid Conformation; D018583:Pliability; D011485:Protein Binding; D011487:Protein Conformation
D002021:Buffers; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; C121766:MRE11 protein, human; D046912:Multiprotein Complexes; C112156:NBN protein, human; D009687:Nuclear Proteins; D000266:Adenylyl Imidodiphosphate; D004247:DNA; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes