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

Science Advances
Suela XhaniGregory Mk Poon

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.

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Citations

Aug 23, 2020·International Journal of Molecular Sciences·Victor LevitskyTatyana Merkulova
Nov 29, 2020·Current Opinion in Structural Biology·Ngaio C SmithJacqueline M Matthews
May 6, 2021·The Journal of Experimental Medicine·Carole Le CozNeil Romberg

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Datasets Mentioned

BETA
X54550

Methods Mentioned

BETA
ubiquitination
nuclear magnetic resonance
NMR
Fluorescence
transfection
PMA
footprinting
electrophoresis
circular
ion exchange chromatography

Software Mentioned

NMRFAM Pine
NMNRFx
NMRFAM
ProtSA
TopSpin
- Sparky
MassLynx

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