Polymer effects modulate binding affinities in disordered proteins

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-09, Vol.116 (39), p.19506-19512
• Main Authors: Vancraenenbroeck, Renee, Harel, Yair S., Zheng, Wenwei, Hofmann, Hagen
• Format: Article
• Language: English
• Subjects: Affinity; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Basic-Leucine Zipper Transcription Factors; Binding; Biological Sciences; Biophysical Phenomena; Cellular communication; Computer simulation; Coupling (molecular); Energy transfer; Fluorescence Resonance Energy Transfer - methods; Homology; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - metabolism; Models, Molecular; Oocytes - metabolism; PNAS Plus; Polymers; Polymers - chemistry; Polymers - metabolism; Protein Binding - physiology; Protein Conformation; Protein Folding; Proteins; Proto-Oncogene Proteins c-myc; Quantitative analysis; Sensitivity; Smad1 Protein; Variations; Xenopus laevis; Xenopus Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1904997116

Structural disorder is widespread in regulatory protein networks. Weak and transient interactions render disordered proteins particularly sensitive to fluctuations in solution conditions such as ion and crowder concentrations. How this sensitivity alters folding coupled binding reactions, however, has not been fully understood. Here, we demonstrate that salt jointly modulates polymer properties and binding affinities of 5 disordered proteins from a transcription factor network. A combination of single-molecule Förster resonance energy transfer experiments, polymer theory, and molecular simulations shows that all 5 proteins expand with increasing ionic strengths due to Debye–Hückel charge screening. Simultaneously, pairwise affinities between the proteins increase by an order of magnitude within physiological salt limits. A quantitative analysis shows that 50% of the affinity increase can be explained by changes in the disordered state. Disordered state properties therefore have a functional relevance even if these states are not directly involved in biological functions. Numerical solutions of coupled binding equilibria with our results show that networks of homologous disordered proteins can function surprisingly robustly in fluctuating cellular environments, despite the sensitivity of its individual proteins.