ArticleBiophysical journal2015
Subdomain interactions foster the design of two protein pairs with ∼80% sequence identity but different folds.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Fold-Switching Proteins.Annual review of biophysics · 2026Review
- Fold-switching proteins.ArXiv · 2025Article
- Proteomic Evidence for Amyloidogenic Cross-Seeding in Fibrinaloid Microclots.International journal of molecular sciences · 2024Article
- Identification of a covert evolutionary pathway between two protein folds.Nature communications · 2023Article
- A review of visualisations of protein fold networks and their relationship with sequence and function.Biological reviews of the Cambridge Philosophical Society · 2023Review
- Reversible switching between two common protein folds in a designed system using only temperature.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Many dissimilar NusG protein domains switch between α-helix and β-sheet folds.Nature communications · 2022Article
- A sequence-based method for predicting extant fold switchers that undergo α-helix ↔ β-strand transitions.Biopolymers · 2021Article
- Predictable fold switching by the SARS-CoV-2 protein ORF9b.Protein science : a publication of the Protein Society · 2021Article
- Exploring the sequence fitness landscape of a bridge between protein folds.PLoS computational biology · 2020Article
- Structure of the Hydrophobic Core Determines the 3D Protein Structure-Verification by Single Mutation Proteins.Biomolecules · 2020Article
- Why Proteins are Big: Length Scale Effects on Equilibria and Kinetics.The protein journal · 2019Review
- Multistep mutational transformation of a protein fold through structural intermediates.Protein science : a publication of the Protein Society · 2018Article
- Structural metamorphism and polymorphism in proteins on the brink of thermodynamic stability.Protein science : a publication of the Protein Society · 2018Review
- Extant fold-switching proteins are widespread.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The role of negative selection in protein evolution revealed through the energetics of the native state ensemble.Proteins · 2016Article
- Studying protein fold evolution with hybrids of differently folded homologs.Protein engineering, design & selection : PEDS · 2015Article
- Structural origins of misfolding propensity in the platelet adhesive von Willebrand factor A1 domain.Biophysical journal · 2015Article
- Two is a pair, three is a network.Biophysical journal · 2015Article
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5 authors.
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Abstract
Metamorphic proteins, including proteins with high levels of sequence identity but different folds, are exceptions to the long-standing rule-of-thumb that proteins with as little as 30% sequence identity adopt the same fold. Which topologies can be bridged by these highly identical sequences remains an open question. Here we bridge two 3-α-helix bundle proteins with two radically different folds. Using a straightforward approach, we engineered the sequences of one subdomain within maltose binding protein (MBP, α/β/α-sandwich) and another within outer surface protein A (OspA, β-sheet) to have high sequence identity (80 and 77%, respectively) with engineered variants of protein G (GA, 3-α-helix bundle). Circular dichroism and nuclear magnetic resonance spectra of all engineered variants demonstrate that they maintain their native conformations despite substantial sequence modification. Furthermore, the MBP variant (80% identical to GA) remained active. Thermodynamic analysis of numerous GA and MBP variants suggests that the key to our approach involved stabilizing the modified MBP and OspA subdomains via external interactions with neighboring substructures, indicating that subdomain interactions can stabilize alternative folds over a broad range of sequence variation. These findings suggest that it is possible to bridge one fold with many other topologies, which has implications for protein folding, evolution, and misfolding diseases.
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