An intrinsically disordered adaptor protein controls the size and composition of EGFR condensates on membranes
- 1MIT
Abstract
Receptor phase separation is common in signaling pathways, yet mechanisms that limit condensate size and drive their dissolution remain poorly understood. For example, phosphorylated EGFR forms large micron-scale condensates in vitro, but assembles into smaller nanoscale clusters in cells, suggesting cellular regulation of condensate size. Here, we show that the intrinsically disordered adaptor protein GAB1 actively dissolves EGFR condensates and re-nucleates smaller, compositionally distinct assemblies in reconstituted supported lipid bilayers and simulations. Dissolution requires unphosphorylated tyrosines within the GAB1 intrinsically disordered region, and tyrosine phosphorylation acts as a regulatory switch that abolishes this activity. GAB1-nucleated assemblies require PH domain-driven oligomerization, which is inhibited by phosphoinositide lipids, linking membrane composition to nucleation. These results uncover two unexpected regulatory features in signaling pathways. First, unphosphorylated tyrosines may function broadly to regulate condensate size or stability, since similar tyrosine-based sequence features are found across hundreds of proteins, including many that function in signal transduction. Additionally, PH domains may play a broader role in protein oligomerization and receptor organization, as an AlphaFold screen reveals dozens of additional PH domains predicted to self-associate. Together, these results establish general mechanisms that function as modular tools for reprogramming signaling through receptor reorganization and may enable new approaches to target such pathways in disease.
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BibTeX
@misc{ullo2026intrinsically,
title = {{An intrinsically disordered adaptor protein controls the size and composition of EGFR condensates on membranes}},
author = {M. F. Ullo and D. E. Tillman and H. Coban and K. G. Stratton and D. D. Baynes and A. Alexander-Katz and L. B. Case},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759085},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759085v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - An intrinsically disordered adaptor protein controls the size and composition of EGFR condensates on membranes
AU - M. F. Ullo
AU - D. E. Tillman
AU - H. Coban
AU - K. G. Stratton
AU - D. D. Baynes
AU - A. Alexander-Katz
AU - L. B. Case
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759085
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759085v1
AB - Receptor phase separation is common in signaling pathways, yet mechanisms that limit condensate size and drive their dissolution remain poorly understood. For example, phosphorylated EGFR forms large micron-scale condensates in vitro, but assembles into smaller nanoscale clusters in cells, suggesting cellular regulation of condensate size. Here, we show that the intrinsically disordered adaptor protein GAB1 actively dissolves EGFR condensates and re-nucleates smaller, compositionally distinct assemblies in reconstituted supported lipid bilayers and simulations. Dissolution requires unphosphorylated tyrosines within the GAB1 intrinsically disordered region, and tyrosine phosphorylation acts as a regulatory switch that abolishes this activity. GAB1-nucleated assemblies require PH domain-driven oligomerization, which is inhibited by phosphoinositide lipids, linking membrane composition to nucleation. These results uncover two unexpected regulatory features in signaling pathways. First, unphosphorylated tyrosines may function broadly to regulate condensate size or stability, since similar tyrosine-based sequence features are found across hundreds of proteins, including many that function in signal transduction. Additionally, PH domains may play a broader role in protein oligomerization and receptor organization, as an AlphaFold screen reveals dozens of additional PH domains predicted to self-associate. Together, these results establish general mechanisms that function as modular tools for reprogramming signaling through receptor reorganization and may enable new approaches to target such pathways in disease.
ER -