ArticleProceedings of the National Academy of Sciences of the United States of America2018
Extant fold-switching proteins are widespread.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers.
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126 citing papers in PubMed.
- Embrace Disorder as a Function: Bio-Informed Biomaterials Design Advanced by Intrinsically Disordered Proteins.Biomimetics (Basel, Switzerland) · 2026Article
- Synthetic sequence alignments as programmable probes of learned conformational landscapes in deep learning protein structure predictors.Bioinformatics (Oxford, England) · 2026Article
- Signatures of protein fold switching in the unfolded state.Biophysical journal · 2026Article
- Navigating the uncharted: AI-driven advances in protein structure, dynamics, interactions and ligand interactions for understudied families.BioData mining · 2026Review
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Surface cues shape procoagulant properties of amyloidogenic microclots.Cell death & disease · 2026Review
- A simple model captures key characteristics of biological non-deterministic genotype-phenotype maps.PLoS computational biology · 2026Article
- Fold-Switching Proteins.Annual review of biophysics · 2026Review
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- Exploration of the structural and functional diversity in the metamorphic RfaH subfamily.bioRxiv : the preprint server for biology · 2026Article
- Wanted: A population genetic theory of biological noise regulation.PLoS genetics · 2026Article
- Disentangling coevolutionary constraints for modeling protein conformational heterogeneity.Communications chemistry · 2026Article
- Unlocking hidden biomolecular conformational landscapes in diffusion models at inference time.ArXiv · 2026Article
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- A dramatic protein fold switch powers a bactericidal nanomachine.bioRxiv : the preprint server for biology · 2026Article
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- Adversarial Sequence Mutations in AlphaFold and ESMFold Reveal Nonphysical Structural Invariance, Confidence Failures, and Concerns for Protein Design.Computational and structural biotechnology journal · 2026Article
- From Atoms to Cells: AI-Based Structure Prediction Fueling Molecular Dynamics Simulations in Computational Structural Biology.Advances in experimental medicine and biology · 2026Review
- Computational Identification of Potential Shape-Shifting Proteins from Structures.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Morpheus: a fragment-based algorithm to predict fold-switching behaviour in proteins across proteomes.Bioinformatics (Oxford, England) · 2025Article
66 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
A central tenet of biology is that globular proteins have a unique 3D structure under physiological conditions. Recent work has challenged this notion by demonstrating that some proteins switch folds, a process that involves remodeling of secondary structure in response to a few mutations (evolved fold switchers) or cellular stimuli (extant fold switchers). To date, extant fold switchers have been viewed as rare byproducts of evolution, but their frequency has been neither quantified nor estimated. By systematically and exhaustively searching the Protein Data Bank (PDB), we found ∼100 extant fold-switching proteins. Furthermore, we gathered multiple lines of evidence suggesting that these proteins are widespread in nature. Based on these lines of evidence, we hypothesized that the frequency of extant fold-switching proteins may be underrepresented by the structures in the PDB. Thus, we sought to identify other putative extant fold switchers with only one solved conformation. To do this, we identified two characteristic features of our ∼100 extant fold-switching proteins, incorrect secondary structure predictions and likely independent folding cooperativity, and searched the PDB for other proteins with similar features. Reassuringly, this method identified dozens of other proteins in the literature with indication of a structural change but only one solved conformation in the PDB. Thus, we used it to estimate that 0.5-4% of PDB proteins switch folds. These results demonstrate that extant fold-switching proteins are likely more common than the PDB reflects, which has implications for cell biology, genomics, and human health.
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