ArticleProceedings of the National Academy of Sciences of the United States of America2012
A thermodynamic definition of protein domains.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. 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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27 citing papers in PubMed.
- Decoding the mechanism governing the structural stability of wheat germ agglutinin and its isolated domains: A combined calorimetric, NMR, and MD simulation study.Protein science : a publication of the Protein Society · 2024Article
- Spectroscopic analysis of the bacterially expressed head domain of rotavirus VP6.Bioscience reports · 2024Article
- The small protein MntS evolved from a signal peptide and acquired a novel function regulating manganese homeostasis in Escherichia coli.Molecular microbiology · 2024Article
- Fluid protein fold space and its implications.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Article
- Assignment of structural domains in proteins using diffusion kernels on graphs.BMC bioinformatics · 2022Article
- Isothermal titration calorimetry of membrane protein interactions: FNR and the cytochrome bBiophysical journal · 2022Article
- Metamorphic proteins under a computational microscope: Lessons from a fold-switching RfaH protein.Computational and structural biotechnology journal · 2022Review
- Structural bioinformatics enhances mechanistic interpretation of genomic variation, demonstrated through the analyses of 935 distinct RAS family mutations.Bioinformatics (Oxford, England) · 2021Article
- Sequence-Based Prediction of Metamorphic Behavior in Proteins.Biophysical journal · 2020Article
- Inaccurate secondary structure predictions often indicate protein fold switching.Protein science : a publication of the Protein Society · 2019Article
- Folding, Assembly, and Persistence: The Essential Nature and Origins of Biopolymers.Journal of molecular evolution · 2018Article
- Extant fold-switching proteins are widespread.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Article
- Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping.Journal of molecular biology · 2017Article
- Competing Pathways and Multiple Folding Nuclei in a Large Multidomain Protein, Luciferase.Biophysical journal · 2017Article
- Frozen in Time: The History of Proteins.Molecular biology and evolution · 2017Article
- Differential Scanning Calorimetry - A Method for Assessing the Thermal Stability and Conformation of Protein Antigen.Journal of visualized experiments : JoVE · 2017Article
- An ambiguity principle for assigning protein structural domains.Science advances · 2017Article
- Ubiquitylation Directly Induces Fold Destabilization of Proteins.Scientific reports · 2016Article
- Untangling a Structurally Resolved Protein Folding Intermediate.Biophysical journal · 2016Article
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2 authors.
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Abstract
Protein domains are conspicuous structural units in globular proteins, and their identification has been a topic of intense biochemical interest dating back to the earliest crystal structures. Numerous disparate domain identification algorithms have been proposed, all involving some combination of visual intuition and/or structure-based decomposition. Instead, we present a rigorous, thermodynamically-based approach that redefines domains as cooperative chain segments. In greater detail, most small proteins fold with high cooperativity, meaning that the equilibrium population is dominated by completely folded and completely unfolded molecules, with a negligible subpopulation of partially folded intermediates. Here, we redefine structural domains in thermodynamic terms as cooperative folding units, based on m-values, which measure the cooperativity of a protein or its substructures. In our analysis, a domain is equated to a contiguous segment of the folded protein whose m-value is largely unaffected when that segment is excised from its parent structure. Defined in this way, a domain is a self-contained cooperative unit; i.e., its cooperativity depends primarily upon intrasegment interactions, not intersegment interactions. Implementing this concept computationally, the domains in a large representative set of proteins were identified; all exhibit consistency with experimental findings. Specifically, our domain divisions correspond to the experimentally determined equilibrium folding intermediates in a set of nine proteins. The approach was also proofed against a representative set of 71 additional proteins, again with confirmatory results. Our reframed interpretation of a protein domain transforms an indeterminate structural phenomenon into a quantifiable molecular property grounded in solution thermodynamics.
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