ArticleThe Journal of biological chemistry2012
An ultra-specific avian antibody to phosphorylated tau protein reveals a unique mechanism for phosphoepitope recognition.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Single-Stranded Variable Fragment Gene Libraries Built for Phage Display: An Updated Review of Design, Selection and Application.Journal of microbiology and biotechnology · 2024Review
- Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status.Molecules (Basel, Switzerland) · 2023Review
- Yeast biopanning against site-specific phosphorylations in tau.Protein engineering, design & selection : PEDS · 2023Article
- Crystal structure of ultra-humanized anti-pTau Fab reveals how germline substitutions humanize CDRs without loss of binding'.Scientific reports · 2022Article
- Sensitive Electrochemical Detection of Phosphorylated-Tau Threonine 231 in Human Serum Using Interdigitated Wave-Shaped Electrode.Biomedicines · 2021Article
- Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.Chemical reviews · 2021Review
- Structural basis for differential recognition of phosphohistidine-containing peptides by 1-pHis and 3-pHis monoclonal antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- High-specificity antibodies and detection methods for quantifying phosphorylated tau from clinical samples.Antibody therapeutics · 2021Review
- Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer.Brain sciences · 2020Review
- Computationally Designed Cyclic Peptides Derived from an Antibody Loop Increase Breadth of Binding for Influenza Variants.Structure (London, England : 1993) · 2020Article
- Effect of Phosphorylation and O-GlcNAcylation on Proline-Rich Domains of Tau.The journal of physical chemistry. B · 2020Article
- Peptidyl-ProlylFrontiers in cell and developmental biology · 2020Review
- Article
- A survival selection strategy for engineering synthetic binding proteins that specifically recognize post-translationally phosphorylated proteins.Nature communications · 2019Article
- The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?Acta neuropathologica communications · 2019Review
- Structural Diversity of Ultralong CDRH3s in Seven Bovine Antibody Heavy Chains.Frontiers in immunology · 2019Article
- A Recombinant Affinity Reagent Specific for a Phosphoepitope of Akt1.International journal of molecular sciences · 2018Article
- Directed evolution of a picomolar-affinity, high-specificity antibody targeting phosphorylated tau.The Journal of biological chemistry · 2018Article
- Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders.Acta neuropathologica · 2018Article
- Tau Antibody Structure Reveals a Molecular Switch Defining a Pathological Conformation of the Tau Protein.Scientific reports · 2018Article
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Authors and funding
25 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Highly specific antibodies to phosphoepitopes are valuable tools to study phosphorylation in disease states, but their discovery is largely empirical, and the molecular mechanisms mediating phosphospecific binding are poorly understood. Here, we report the generation and characterization of extremely specific recombinant chicken antibodies to three phosphoepitopes on the Alzheimer disease-associated protein tau. Each antibody shows full specificity for a single phosphopeptide. The chimeric IgG pT231/pS235_1 exhibits a K(D) of 0.35 nm in 1:1 binding to its cognate phosphopeptide. This IgG is murine ortholog-cross-reactive, specifically recognizing the pathological form of tau in brain samples from Alzheimer patients and a mouse model of tauopathy. To better understand the underlying binding mechanisms allowing such remarkable specificity, we determined the structure of pT231/pS235_1 Fab in complex with its cognate phosphopeptide at 1.9 Å resolution. The Fab fragment exhibits novel complementarity determining region (CDR) structures with a "bowl-like" conformation in CDR-H2 that tightly and specifically interacts with the phospho-Thr-231 phosphate group, as well as a long, disulfide-constrained CDR-H3 that mediates peptide recognition. This binding mechanism differs distinctly from either peptide- or hapten-specific antibodies described to date. Surface plasmon resonance analyses showed that pT231/pS235_1 binds a truly compound epitope, as neither phosphorylated Ser-235 nor free peptide shows any measurable binding affinity.
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