ArticleProceedings of the National Academy of Sciences of the United States of America2014
Understanding the frustration arising from the competition between function, misfolding, and aggregation in a globular protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 54 citations in OpenAlex.
- Dissecting the Structural Features of Folding Asymmetry and Transient Misfolding in a Multidomain PDZ Scaffold.Small science · 2026Article
- Understanding domain swapping in the c-Src SH3 domain through hinge-loop mutagenesis.Acta crystallographica. Section D, Structural biology · 2025Article
- Frustration in physiology and molecular medicine.Molecular aspects of medicine · 2025Review
- Biomolecular Condensates Can Enhance Homotypic RNA Clustering.bioRxiv : the preprint server for biology · 2025Article
- Automated optimisation of solubility and conformational stability of antibodies and proteins.Nature communications · 2023Article
- Characterization of early and late transition states of the folding pathway of a SH2 domain.Protein science : a publication of the Protein Society · 2022Article
- An Outlook on the Complexity of Protein Morphogenesis in Health and Disease.Frontiers in molecular biosciences · 2022Review
- Converging experimental and computational views of the knotting mechanism of a small knotted protein.Biophysical journal · 2021Article
- Fuzziness and Frustration in the Energy Landscape of Protein Folding, Function, and Assembly.Accounts of chemical research · 2021Review
- Studying GGDEF Domain in the Act: Minimize Conformational Frustration to Prevent Artefacts.Life (Basel, Switzerland) · 2021Article
- The Effect of ProlineInternational journal of molecular sciences · 2019Article
- Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40).ACS nano · 2019Article
- Localizing Frustration in Proteins Using All-Atom Energy Functions.The journal of physical chemistry. B · 2019Article
- Thermodynamics of protein folding: methodology, data analysis and interpretation of data.European biophysics journal : EBJ · 2019Article
- A structurally heterogeneous transition state underlies coupled binding and folding of disordered proteins.The Journal of biological chemistry · 2019Article
- Stability of an aggregation-prone partially folded state of human profilin-1 correlates with aggregation propensity.The Journal of biological chemistry · 2018Article
- Elucidation of the structural stability and dynamics of heterogeneous intermediate ensembles in unfolding pathway of the N-terminal domain of TDP-43.RSC advances · 2018Article
- Deciphering the dark proteome of Chikungunya virus.Scientific reports · 2018Article
- Frustration, function and folding.Current opinion in structural biology · 2018Review
- Smoothing a rugged protein folding landscape by sequence-based redesign.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Folding and function may impose different requirements on the amino acid sequences of proteins, thus potentially giving rise to conflict. Such a conflict, or frustration, can result in the formation of partially misfolded intermediates that can compromise folding and promote aggregation. We investigate this phenomenon by studying frataxin, a protein whose normal function is to facilitate the formation of iron-sulfur clusters but whose mutations are associated with Friedreich's ataxia. To characterize the folding pathway of this protein we carry out a Φ-value analysis and use the resulting structural information to determine the structure of the folding transition state, which we then validate by a second round of rationally designed mutagenesis. The analysis of the transition-state structure reveals that the regions involved in the folding process are highly aggregation-prone. By contrast, the regions that are functionally important are partially misfolded in the transition state but highly resistant to aggregation. Taken together, these results indicate that in frataxin the competition between folding and function creates the possibility of misfolding, and that to prevent aggregation the amino acid sequence of this protein is optimized to be highly resistant to aggregation in the regions involved in misfolding.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.