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Flexible nets: The roles of intrinsic disorder in protein interaction networks
Open accessAbstract
Proteins participate in complex sets of interactions that represent the mechanistic foundation for much of the physiology and function of the cell. These protein–protein interactions are organized into exquisitely complex networks. The architecture of protein–protein interaction networks was recently proposed to be scale‐free, with most of the proteins having only one or two connections but with relatively fewer ‘hubs’ possessing tens, hundreds or more links. The high level of hub connectivity must somehow be reflected in protein structure. What structural quality of hub proteins enables them to interact with large numbers of diverse targets? One possibility would be to employ binding regions that have the ability to bind multiple, structurally diverse partners. This trait can be imparted by the incorporation of intrinsic disorder in one or both partners. To illustrate the value of such contributions, this review examines the roles of intrinsic disorder in protein network architecture. We show that there are three general ways that intrinsic disorder can contribute: First, intrinsic disorder can serve as the structural basis for hub protein promiscuity; secondly, intrinsically disordered proteins can bind to structured hub proteins; and thirdly, intrinsic disorder can provide flexible linkers between functional domains with the linkers enabling mechanisms that facilitate binding diversity. An important research direction will be to determine what fraction of protein–protein interaction in regulatory networks relies on intrinsic disorder.
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“Many IDPs/IDRs are capable of at least partial ordering upon interaction with specific partners [7–18].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [10]
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Metadata
- Authors
- Dunker, A. K., Cortese, M. S., Romero, P., Iakoucheva, L. M., & Uversky, V. N.
- Affiliations
- Indiana University Indianapolis (US)
- Indiana University Bloomington (US)
- Rockefeller University (US)
- Russian Academy of Sciences (RU)
- Corresponding author
- Dunker, A. Keith
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2005-10
- Volume
- 272
- Issue
- 20
- Pages
- 5129-5148
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W1975121208
- Cited by
- 1,122
- References
- 203
- Citations by year
- 2026: 29 · 2025: 30 · 2024: 32 · 2023: 43 · 2022: 49 · 2021: 41 · 2020: 62 · 2019: 41 · 2018: 38 · 2017: 69 · 2016: 53 · 2015: 60 · 2014: 75 · 2013: 61 · 2012: 80
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
- Funders
- National Science Foundation (0444818)
- National Institutes of Health
- U.S. National Library of Medicine (R01LM007688, 1 R01 LM007688-0A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- intrinsic disorder, intrinsically disordered proteins, protein-protein interaction network, scale-free networks, hub proteins, binding promiscuity, flexible linkers, protein structure, regulatory networks
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Binding Sites, Calmodulin, Cell Physiological Phenomena, Humans, Models, Biological, Models, Molecular, Protein Binding, Protein Conformation, Proteins, Protein Structure, Tertiary, Cyclin-Dependent Kinases, HMGA Proteins, Glycogen Synthase Kinase 3, Xeroderma Pigmentosum Group A Protein
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