Mre11-Rad50 complex crystals suggest molecular calisthenics

Abstract

Recently published crystal structures of different Mre11 and Rad50 complexes show the arrangement of these proteins and imply dramatic ligand-induced rearrangements with important functional consequences.

Figure 1

Schematic representation of the MR complex. Rad50 molecules are depicted in orange with a globular ATPase domain and part of the coiled coil. ATP is represented by a blue pentagon. The ATP binding domains of Rad50 are depicted in dark orange. Mre11 is shown in green. Its globular dimerization domain is connected through a linker to its HLH domain, which interacts with the Rad50 coiled coils. The Mre11 DNA binding domain is depicted in dark green. All complexes are oriented with respect to a fixed Mre11 orientation. (A, B) In previous models (indicated by “Old”) Mre11 was imagined to be located between the Rad50 coiled coils. The ATPase binding pockets of the Rad50 monomers are pointing towards each other and their dimerization upon ATP binding can occur with minimal relative movement. (C, D) In the “New” model, in the absence of ATP, the Mre11 globular domains including its DNA binding and nuclease active sites are located between the Rad50 ATPase domains, whose ATP binding pockets are facing away from each other in an “open” complex. Upon ATP binding a dramatic rearrangement within the MR complex is required to dimerize the ATPase domains resulting in a “closed” complex.

Figure 2

Interaction of the MR complex with DNA. Mre11, Rad50 and ATP are depicted as in Figure 1. DNA strands are shown in red. (A) In the “open” complex arrangement, in the absence of ATP, the DNA binding site of Mre11 can accommodate double-stranded DNA, while Rad50 is unlikely to bind DNA. (B) In the “closed” complex conformation upon ATP binding, Rad50 can engage double-stranded DNA, while the Mre11 DNA binding site is more constrained and now possibly limited to binding single-stranded DNA.

Figure 3

Nucleotide binding to Rad50 modulates the Mre11 dimer interface and relative orientation of nuclease active sites. Overlay of the Mre11 globular domains (including the nuclease and capping domains) as observed in different crystal structures [4,5,8]. The structures are superimposed by fixing the position of one dimer-interface helix from one subunit. Mre11 bound to DNA (3DSD.pdb) is depicted in green, Mre11 in the MR complex with open Rad50 (3QG5.pdb) is depicted in blue and Mre11 in the MR complex with closed Rad50 (3AVO.pdb) is depicted in yellow. The nuclease active site histidine involved in transition state stabilization is indicated with a colored sphere. The displacement of this histidine between the different structures is indicated. The three structures clearly also differ with respect to a rotation of one subunit relative to the other.