Intrinsic disorder controls two functionally distinct dimers of the master transcription factor PU.1

Authors

• Suela Xhani, Department of Chemistry, Georgia State University
• Sangchoon Lee, Department of Chemistry, Georgia
• Hye Mi Kim, Department of Chemistry, Georgia
• Siming Wang, Department of Chemistry, Georgia
• Shingo Esaki, Department of Chemistry, Georgia
• Van L. T. Ha, Department of Chemistry, Georgia
• Mahtab Khanezarrin, Department of Chemistry, Georgia
• Giselle L. Fernandez, Department of Chemistry, Georgia
• Amanda V. Albrecht, Department of Chemistry, Georgia
• James Aramini, CUNY Advanced Science Research CenterFollow
• Markus W. Germann, Department of Chemistry, Georgia
• Gregory M. K. Poon, Department of Chemistry, Georgia

Document Type

Article

Publication Date

2-21-2020

Abstract

Transcription factors comprise a major reservoir of conformational disorder in the eukaryotic proteome. The hematopoietic master regulator PU.1 presents a well-defined model of the most common configuration of intrinsically disordered regions (IDRs) in transcription factors. We report that the structured DNA binding domain (DBD) of PU.1 regulates gene expression via antagonistic dimeric states that are reciprocally controlled by cognate DNA on the one hand and by its proximal anionic IDR on the other. The two conformers are mediated by distinct regions of the DBD without structured contributions from the tethered IDRs. Unlike DNA-bound complexes, the unbound dimer is markedly destabilized. Dimerization without DNA is promoted by progressive phosphomimetic substitutions of IDR residues that are phosphorylated in immune activation and stimulated by anionic crowding agents. These results suggest a previously unidentified, nonstructural role for charged IDRs in conformational control by mitigating electrostatic penalties that would mask the interactions of highly cationic DBDs.

Comments

This article was originally published in Science Advances, available at http://dx.doi.org/10.1126/sciadv.aay3178

This work is distributed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).