Dimerization, but not phosphothreonine binding, is conserved between the forkhead-associated domains of Drosophila MU2 and human MDC1

Mutator 2 (MU2) in Drosophila melanogaster has been proposed to be the ortholog of human MDC1, a key mediator in DNA damage response. The forkhead-associated (FHA) domain of MDC1 is a dimerization module regulated by trans binding to phosphothreonine 4 from another molecule. Here we present the crystal structure of the MU2 FHA domain at 1.9 Å resolution, revealing its evolutionarily conserved role in dimerization. As compared to the MDC1 FHA domain, the MU2 FHA domain dimerizes using a different and more stable interface and contains a degenerate phosphothreonine-binding pocket. Our results suggest that the MU2 dimerization is constitutive and lacks phosphorylation-mediated regulation.Structured summary of protein interactionsMU2 and MU2bind by cosedimentation in solution (View interaction)MU2 and MU2bind by X-ray crystallography (View interaction)MU2 and MU2bind by molecular sieving (View interaction)

► The crystal structure of the MU2 FHA domain reveals a dimer. ► The FHA dimer interface is different between MU2 and MDC1. ► The phosphothreonine-binding pocket of MU2 FHA is degenerate. ► MU2 dimerization is constitutive and lacks phosphorylation-mediated regulation.