Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity
Open accessAbstract
Regulation of biological processes often involves phosphorylation of intrinsically disordered protein regions, thereby modulating protein interactions. Initiation of DNA replication in yeast requires elimination of the cyclin-dependent kinase inhibitor Sic1 via the SCF Cdc4 ubiquitin ligase. Intriguingly, the substrate adapter subunit Cdc4 binds to Sic1 only after phosphorylation of a minimum of any six of the nine cyclin-dependent kinase sites on Sic1. To investigate the physical basis of this ultrasensitive interaction, we consider a mean-field statistical mechanical model for the electrostatic interactions between a single receptor site and a conformationally disordered polyvalent ligand. The formulation treats phosphorylation sites as negative contributions to the total charge of the ligand and addresses its interplay with the strength of the favorable ligand–receptor contact. Our model predicts a threshold number of phosphorylation sites for receptor–ligand binding, suggesting that ultrasensitivity in the Sic1–Cdc4 system may be driven at least in part by cumulative electrostatic interactions. This hypothesis is supported by experimental affinities of Cdc4 for Sic1 fragments with different total charges. Thus, polyelectrostatic interactions may provide a simple yet powerful framework for understanding the modulation of protein interactions by multiple phosphorylation sites in disordered protein regions.
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Some IDPs/IDRs may remain unfolded and dynamic even in the bound state, creating fuzzy complexes.
“Some IDPs/IDRs may remain unfolded and dynamic even in the bound state [19–23], creating fuzzy complexes (Fig. 1) [24, 25].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [20]
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- Authors
- Borg, M., Mittag, T., Pawson, T., Tyers, M., Forman-Kay, J. D., & Chan, H. S.
- Affiliations
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Mount Sinai Hospital (CA)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-06-05
- Volume
- 104
- Issue
- 23
- Pages
- 9650-9655
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1887549
- OpenAlex
- W2164220403
- Cited by
- 245
- References
- 56
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 12 · 2023: 5 · 2022: 10 · 2021: 16 · 2020: 7 · 2019: 13 · 2018: 20 · 2017: 18 · 2016: 13 · 2015: 15 · 2014: 15 · 2013: 15 · 2012: 18
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sweden-America Foundation
- University of Toronto
- Canadian Institutes of Health Research
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Electrostatics and Colloid Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- ultrasensitivity, intrinsically disordered proteins, phosphorylation, Sic1, Cdc4, SCF ubiquitin ligase, cyclin-dependent kinases, ligand-receptor interactions, electrostatic interactions, DNA replication initiation
- MeSH terms
- DNA Replication, Ligands, Models, Biological, Phosphorylation, Protein Binding, Yeasts, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases, F-Box Proteins, Cyclin-Dependent Kinase Inhibitor Proteins, Protein Interaction Domains and Motifs, Static Electricity
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