Schematic representation of the organization of the Mre11 and Rad50 domains in an M/R complex.
(A) Domain architecture of the Mre11 and Rad50 proteins. The nuclease domain of Mre11 is located at the N-terminus of the protein, while the capping domain and proximal helix–loop–helix Rad50 binding regions are located in the C-terminus of the protein adjacent to the DNA binding domains (DBD). N-terminal nucleotide-binding domain (N-NBD, ATPase-N) and C-terminal (C-NBD, ATPase-C) ATPase domains (in orange) are separated by a long antiparallel coiled coil region with a central zinc-hook domain (red). The Mre11 helix–loop–helix binding regions, proximal to the ATPase domains are indicated in blue. When folded along the zinc hook domain, the two domains compose a single catalytic ABC ATPase head from which a rod-like coiled-coil protrudes [21]. (Right) Schematic showing organization of the M/R complex: the two globular Rad50 NBD ATPase domains harbouring the Walker A and Walker B motifs, respectively (orange) are connected via the long coiled-coil region (black) which bends at the central ‘zinc-hook’ motif (red). The Mre11 nuclease (blue) interacts with the Rad50 catalytic domains via the ‘capping’ domain (Cap) and helix–loop–helix regions (hlh), which extend from the core nucleolytic domain (Nuc). (B–E) The M/R complex typically arranges as a tetramer (although higher order assemblies are possible [42,43], either via interactions at the zinc-hook (B) or by association of the catalytic globular domains (C,D). The ring-shaped arrangement can form when the intramolecular associations are simultaneously formed at both the Rad50 zinc-hooks and the Mre11 globular domains (D). (E) Upon ATP binding the Rad50 globular domains are brought together resulting in the Rad50 coiled-coils associating to form an extended, rigid conformation that is thought to promote chromosomal bridging via association of the zinc-hooks between two complexes on homologous chromosomes. (F) A distance of 1200 Å (two-times 600 Å) could plausibly be bridged by the human M/R complex, or 600–670 Å by the archaeal complex (Pyrococcus furiosus or Sulfolobus acidocaldarius, respectively) or 490 Å (two-times 245 Å) by the E. coli homologous complex SbcCD, while the distance for bacteriophage coils would be shorter still (two-times 100 Å).