The modular architecture of protein–protein binding interfaces
Open accessAbstract
Protein-protein interactions are essential for life. Yet, our understanding of the general principles governing binding is not complete. In the present study, we show that the interface between proteins is built in a modular fashion; each module is comprised of a number of closely interacting residues, with few interactions between the modules. The boundaries between modules are defined by clustering the contact map of the interface. We show that mutations in one module do not affect residues located in a neighboring module. As a result, the structural and energetic consequences of the deletion of entire modules are surprisingly small. To the contrary, within their module, mutations cause complex energetic and structural consequences. Experimentally, this phenomenon is shown on the interaction between TEM1-beta-lactamase and beta-lactamase inhibitor protein (BLIP) by using multiple-mutant analysis and x-ray crystallography. Replacing an entire module of five interface residues with Ala created a large cavity in the interface, with no effect on the detailed structure of the remaining interface. The modular architecture of binding sites, which resembles human engineering design, greatly simplifies the design of new protein interactions and provides a feasible view of how these interactions evolved.
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Protein-protein interfaces are characterized by hot spots or hot regions rather than even contribution across all contact areas.
“Protein-protein interfaces are characterized by the existence of hot spots or ‘hot regions’ in interacting regions instead of an even contribution across all contact areas.371,476,487,492–495”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [494]
The self-supervised learning scheme enables the geometric encoder to capture different patterns (e.g., solvent accessibilities) between interface and non-interface residues.
“indicating that our self-supervised learning scheme enables the geometric encoder to capture the different patterns (e.g., solvent accessibilities [26]) between interface and the non-interface residues.”
From Deep geometric representations for modeling effects of mutations on protein-protein binding affinity (2021) · cites this paper as [26]
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- Authors
- Reichmann, D., Rahat, O., Albeck, S., Meged, R., Dym, O., & Schreiber, G.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Schreiber, G.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-12-23
- Volume
- 102
- Issue
- 1
- Pages
- 57-62
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC544062
- OpenAlex
- W2165319219
- Cited by
- 239
- References
- 35
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 12 · 2015: 7 · 2014: 12 · 2013: 11 · 2012: 11
- FWCI
- 5.68
- 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)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- protein-protein interaction, binding interface, modular architecture, module boundaries, BLIP
- MeSH terms
- Bacterial Proteins, beta-Lactamases, Binding Sites, Models, Molecular, Mutation, Protein Binding, Proteins, Thermodynamics, Protein Structure, Tertiary
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