Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins
Open accessAbstract
Transcription factors and other allosteric cell signaling proteins contain a disproportionate number of domains or segments that are intrinsically disordered (ID) under native conditions. In many cases folding of these segments is coupled to binding with one or more of their interaction partners, suggesting that intrinsic disorder plays an important functional role. Despite numerous hypotheses for the role of ID domains in regulation, a mechanistic model has yet to be established that can quantitatively assess the importance of intrinsic disorder for intramolecular site-to-site communication, the hallmark property of allosteric proteins. Here, we present such a model and show that site-to-site allosteric coupling is maximized when intrinsic disorder is present in the domains or segments containing one or both of the coupled binding sites. This result not only explains the prevalence of ID domains in regulatory proteins, it also calls into question the classical mechanical view of energy propagation in proteins, which predicts that site-to-site coupling would be maximized when a well defined pathway of folded structure connects the two sites. Furthermore, in showing that the coupling mechanism conferred by intrinsic disorder is robust and independent of the network of interactions that physically link the coupled sites, unique insights are gained into the energetic ground rules that govern site-to-site communication in all proteins.
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The presence of intrinsically disordered regions increases the potential for allosteric regulation.
“Indeed, the presence of intrinsically disordered regions increases the potential for allosteric regulation [32, 33].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [33]
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- Authors
- Hilser, V. J., & Thompson, E. B.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Stanford Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-05-15
- Volume
- 104
- Issue
- 20
- Pages
- 8311-8315
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1895946
- OpenAlex
- W2087395511
- Cited by
- 406
- References
- 28
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 9 · 2023: 20 · 2022: 15 · 2021: 14 · 2020: 24 · 2019: 24 · 2018: 26 · 2017: 18 · 2016: 20 · 2015: 30 · 2014: 27 · 2013: 22 · 2012: 31
- FWCI
- 10.08
- 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
- National Science Foundation (0446050)
- National Institutes of Health
- National Institute of General Medical Sciences (GM-13747, R01GM063747)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- intrinsically disordered regions, allosteric communication, transcription factors, protein folding, allosteric regulation, protein-protein binding
- MeSH terms
- Allosteric Regulation, Models, Biological, Proteins, Thermodynamics, Protein Structure, Tertiary
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