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Abstract
p53 is a representative transcription factor that activates multiple target genes. To realize stimulus-dependent specificities, p53 has to recognize targets with structural variety, of which molecular mechanisms are largely unknown. Here, we conducted a series of long-time scale (totally more than 100-ms) coarse-grained molecular dynamics simulations, uncovering structure and dynamics of full-length p53 tetramer that recognizes its response element (RE). We obtained structures of a full-length p53 tetramer that binds to the RE, which is strikingly different from the structure of p53 at search. These structures are not only consistent with previous low-resolution or partial structural information, but also give access to previously unreachable detail, such as the preferential distribution of intrinsically disordered regions, the contacts between core domains, the DNA bending, and the connectivity of linker regions. We also explored how the RE variation affects the structure of the p53-RE complex. Further analysis of simulation trajectories revealed how p53 finds out the RE and how post-translational modifications affect the search mechanism.
Highlights
P53 is a representative transcription factor that activates multiple target genes
Neutralizing negative charges in the C-terminal domain (CTD) changes the search mechanism from 1D-sliding to 3D-diffusion, but still retaining essentially the same sequential recognition model and the final complex structure. This result indicates that post-translational modifications of the CTD modulate the binding kinetics, necessitating the future in vitro and in vivo assays in which they monitor the relationship between post-translational modifications of the CTD and transactivation kinetics
We employed a coarse-grained representation, where, each amino acid in p53 is represented by one bead located at Cα position and each nucleotide is approximated by three beads, each representing phosphate, sugar, and base
Summary
P53 is a representative transcription factor that activates multiple target genes. To realize stimulusdependent specificities, p53 has to recognize targets with structural variety, of which molecular mechanisms are largely unknown. We obtained structures of a full-length p53 tetramer that binds to the RE, which is strikingly different from the structure of p53 at search These structures are consistent with previous low-resolution or partial structural information, and give access to previously unreachable detail, such as the preferential distribution of intrinsically disordered regions, the contacts between core domains, the DNA bending, and the connectivity of linker regions. As for the low-resolution structure, Tidow et al modeled a full-length p53 tetramer binding to the RE without spacer using cryo-electron microscopy[14] They have not resolved the structure of the full-length p53 tetramer binding to the RE with spacers, from which we can get insight into the molecular mechanism for the full-length p53 to recognize the varying REs. Coarse-grained molecular dynamics simulation studies of our and other groups have greatly contributed to reveal molecular mechanisms of this flexible huge molecule. Khazanov et al revealed inter-domain cross talks of p53 in the search mode at relatively low salt condition[15] by utilizing native structure based one-bead-one-amino-acid protein model[16], frozen three-beads-one-nucleotide DNA model, and simple protein-DNA interaction model that imposes only electrostatic interaction and excluded volume www.nature.com/scientificreports/
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