Related Experiment Video
Updated: Jun 18, 2025
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High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy
Published on: February 7, 2019
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Charge Relaying within a Phospho-Motif Rescue Binding Competency of a Disordered Transcription Factor
Jordan A P McIvor1, Danaé S Larsen1, Davide Mercadante1
1School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand.
Journal of Chemical Information and Modeling
|July 29, 2024
Summary
Phosphorylation typically reduces protein binding affinity. However, this study shows that proximal electrostatic interactions can maintain binding competency in phosphorylated proteins, revealing a new regulatory mechanism for intrinsically disordered proteins.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Structural disorder in proteins is crucial for cellular signaling, enabling promiscuous interactions.
- The nuclear coactivator binding domain (NCBD) of CBP/p300 is a model for such promiscuity.
- Phosphorylation of NCBD via long-range electrostatics was previously shown to cause compaction and reduce binding affinity.
Purpose of the Study:
- To investigate the impact of short-range electrostatics on the NCBD conformational ensemble.
- To understand how proximal interactions modulate the effects of phosphorylation on NCBD binding competency.
Main Methods:
- Extensive molecular simulations were employed.
- Interactions between phosphorylated serine and conserved positive charges in the NCBD phospho-motif were monitored.
Main Results:
- Short-range electrostatic interactions, unlike long-range ones, can reshape the NCBD ensemble.
- These proximal interactions rescue the binding competency of phosphorylated NCBD.
- The findings highlight a potential regulatory role for conserved positive charges in phospho-motifs.
Conclusions:
- Proximal electrostatics offer a mechanism to dampen phosphorylation's effects on intrinsically disordered proteins.
- This regulation fine-tunes binding affinity for various cellular partners.
- Conserved charges in phospho-motifs may act as a molecular relay for phosphorylation-mediated signaling.
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