Charge Relaying within a Phospho-Motif Rescue Binding Competency of a Disordered Transcription Factor

Structural disorder in proteins is central to cellular signaling, where conformational plasticity equips molecules to promiscuously interact with different partners. By engaging with multiple binding partners via the rearrangement of its three helices, the nuclear coactivator binding domain (NCBD) o...

Full description

Saved in:
Bibliographic Details
Published in:Journal of chemical information and modeling 2024-08, Vol.64 (15), p.6041-6052
Main Authors: McIvor, Jordan A. P., Larsen, Danaé S., Mercadante, Davide
Format: Article
Language:English
Subjects:
Affinity
Binding
Cellular structure
Computational Biochemistry
Electrostatics
Helices
Phosphorylation
Plastic foam
Proteins
Relaying
Residues
Transcription factors
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Structural disorder in proteins is central to cellular signaling, where conformational plasticity equips molecules to promiscuously interact with different partners. By engaging with multiple binding partners via the rearrangement of its three helices, the nuclear coactivator binding domain (NCBD) of the CBP/p300 transcription factor is a paradigmatic example of promiscuity. Recently, molecular simulations and experiments revealed that, through the establishment of long-range electrostatic interactions, intended as salt-bridges formed between the post-translationally inserted phosphate and positively charged residues in helix H3 of NCBD, phosphorylation triggers NCBD compaction, lowering its affinity for binding partners. By means of extensive molecular simulations, we here investigated the effect of short-range electrostatics on the conformational ensemble of NCBD, by monitoring the interactions between a phosphorylated serine and conserved positively charged residues within the NCBD phospho-motif. We found that empowering proximal electrostatic interactions, as opposed to long-range electrostatics, can reshape the NCBD ensemble rescuing the binding competency of phosphorylated NCBD. Given the conservation of positive charges in phospho-motifs, proximal electrostatic interactions might dampen the effects of phosphorylation and act as a relay to regulate phosphorylated intrinsically disordered proteins, ultimately tuning the binding affinity for different cellular partners.
ISSN:1549-9596
1549-960X
1549-960X
DOI:10.1021/acs.jcim.4c00286