Autoinhibitory mechanisms of ERG studied by molecular dynamics simulations

Abstract

ERG, an ETS-family transcription factor, acts as a regulator of differentiation of early hematopoietic cells. It contains an autoinhibitory domain, which negatively regulates DNA-binding. The mechanism of autoinhibitory is still illusive. To understand the mechanism, we study the dynamical properties of ERG protein by molecular dynamics simulations. These simulations suggest that DNA binding autoinhibition associates with the internal dynamics of ERG. Specifically, we find that (1), The N-C terminal correlation in the inhibited ERG is larger than that in uninhibited ERG that contributes to the autoinhibition of DNA-binding. (2), DNA-binding changes the property of the N-C terminal correlation from being anti-correlated to correlated, that is, changing the relative direction of the correlated motions and (3), For the Ets-domain specifically, the inhibited and uninhibited forms exhibit essentially the same dynamics, but the binding of the DNA decreases the fluctuation of the Ets-domain. We also find from PCA analysis that the three systems, even with quite different dynamics, do have highly similar free energy surfaces, indicating that they share similar conformations.

ERG-Mediated Cell Invasion: A Link between Development and Tumorigenesis

“…These inhibitory domains inhibit the activity of the ETS domain by decreasing the affinity of ERG for DNA, but they do not fully abolish the DNA-binding activity. Further molecular dynamics simulations show that the partial contact of DNA with autoinhibited ERG triggers a change in protein dynamics to fully relieve the autoinhibition [20]. However, this mechanism does not necessarily exclude the role of posttranslational modifications in regulating ERG DNA binding.…”