ArticleJournal of molecular biology2015
Structure of a single-chain Fv bound to the 17 N-terminal residues of huntingtin provides insights into pathogenic amyloid formation and suppression.
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 14 papers.
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Who cites it
14 citing papers in PubMed, 26 citations in OpenAlex.
- Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease.Nature communications · 2024Article
- Integrative determination of the atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington's disease.bioRxiv : the preprint server for biology · 2024Article
- Emerging Therapies for Huntington's Disease - Focus on N-Terminal Huntingtin and Huntingtin Exon 1.Biologics : targets & therapy · 2022Review
- Antibody Fragments as Tools for Elucidating Structure-Toxicity Relationships and for Diagnostic/Therapeutic Targeting of Neurotoxic Amyloid Oligomers.International journal of molecular sciences · 2020Review
- Engineered Extracellular Vesicles/Exosomes as a New Tool against Neurodegenerative Diseases.Pharmaceutics · 2020Review
- Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington's disease.Experimental biology and medicine (Maywood, N.J.) · 2019Review
- The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract.The Journal of biological chemistry · 2018Article
- Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.Nature communications · 2018Article
- Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Silk micrococoons for protein stabilisation and molecular encapsulation.Nature communications · 2017Article
- Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core.Nature communications · 2017Article
- Recombinant Antibody Fragments for Neurodegenerative Diseases.Current neuropharmacology · 2017Review
- Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes.Biochimica et biophysica acta · 2016Review
- Protein Folding and Mechanisms of Proteostasis.International journal of molecular sciences · 2015Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Huntington's disease is triggered by misfolding of fragments of mutant forms of the huntingtin protein (mHTT) with aberrant polyglutamine expansions. The C4 single-chain Fv antibody (scFv) binds to the first 17 residues of huntingtin [HTT(1-17)] and generates substantial protection against multiple phenotypic pathologies in situ and in vivo. We show in this paper that C4 scFv inhibits amyloid formation by exon1 fragments of huntingtin in vitro and elucidate the structural basis for this inhibition and protection by determining the crystal structure of the complex of C4 scFv and HTT(1-17). The peptide binds with residues 3-11 forming an amphipathic helix that makes contact with the antibody fragment in such a way that the hydrophobic face of this helix is shielded from the solvent. Residues 12-17 of the peptide are in an extended conformation and interact with the same region of another C4 scFv:HTT(1-17) complex in the asymmetric unit, resulting in a β-sheet interface within a dimeric C4 scFv:HTT(1-17) complex. The nature of this scFv-peptide complex was further explored in solution by high-resolution NMR and physicochemical analysis of species in solution. The results provide insights into the manner in which C4 scFv inhibits the aggregation of HTT, and hence into its therapeutic potential, and suggests a structural basis for the initial interactions that underlie the formation of disease-associated amyloid fibrils by HTT.
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