ArticleJournal of molecular biology2015
Conformation-dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing.
Article in Journal of molecular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 53 citations in OpenAlex.
- Prion propagation is controlled by discrete structural regions of PrP rather than overall stability.The Journal of biological chemistry · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Genetically EncodedACS synthetic biology · 2025Article
- Characterization of variably protease-sensitive prionopathy by capillary electrophoresis.Scientific reports · 2024Article
- Prion protein E219K polymorphism: from the discovery of the KANNO blood group to interventions for human prion disease.Frontiers in neurology · 2024Review
- Mutational scan inferred binding energetics and structure in intrinsically disordered protein CcdA.Protein science : a publication of the Protein Society · 2023Article
- Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.JCI insight · 2022Article
- Massively parallel DNA target capture using long adapter single stranded oligonucleotide (LASSO) probes assembled through a novel DNA recombinase mediated methodology.Biotechnology journal · 2022Article
- An overview of methods for the structural and functional mapping of epitopes recognized by anti-SARS-CoV-2 antibodies.RSC chemical biology · 2021Review
- Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy.Pathogens (Basel, Switzerland) · 2021Article
- A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes.Nature communications · 2021Article
- Review
- DropSynth 2.0: high-fidelity multiplexed gene synthesis in emulsions.Nucleic acids research · 2020Article
- Protein tolerance to random circular permutation correlates with thermostability and local energetics of residue-residue contacts.Protein engineering, design & selection : PEDS · 2019Article
- MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect.Genome biology · 2019Article
- A Bioluminescent Cell Assay to Quantify Prion Protein Dimerization.Scientific reports · 2018Article
- Pro region engineering of nerve growth factor by deep mutational scanning enables a yeast platform for conformational epitope mapping of anti-NGF monoclonal antibodies.Biotechnology and bioengineering · 2018Article
- Circular permutation profiling by deep sequencing libraries created using transposon mutagenesis.Nucleic acids research · 2018Article
- Characterizing Protein-Protein Interactions Using Deep Sequencing Coupled to Yeast Surface Display.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Deep sequencing methods for protein engineering and design.Current opinion in structural biology · 2017Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Prion diseases are caused by a structural rearrangement of the cellular prion protein, PrP(C), into a disease-associated conformation, PrP(Sc), which may be distinguished from one another using conformation-specific antibodies. We used mutational scanning by cell-surface display to screen 1341 PrP single point mutants for attenuated interaction with four anti-PrP antibodies, including several with conformational specificity. Single-molecule real-time gene sequencing was used to quantify enrichment of mutants, returning 26,000 high-quality full-length reads for each screened population on average. Relative enrichment of mutants correlated to the magnitude of the change in binding affinity. Mutations that diminished binding of the antibody ICSM18 represented the core of contact residues in the published crystal structure of its complex. A similarly located binding site was identified for D18, comprising discontinuous residues in helix 1 of PrP, brought into close proximity to one another only when the alpha helix is intact. The specificity of these antibodies for the normal form of PrP likely arises from loss of this conformational feature after conversion to the disease-associated form. Intriguingly, 6H4 binding was found to depend on interaction with the same residues, among others, suggesting that its ability to recognize both forms of PrP depends on a structural rearrangement of the antigen. The application of mutational scanning and deep sequencing provides residue-level resolution of positions in the protein-protein interaction interface that are critical for binding, as well as a quantitative measure of the impact of mutations on binding affinity.
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Registered trials
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.