Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin
This article presents experimental evidence and computed molecular models of a potential interaction between receptor domain D5 of TrkB with the carboxyl-terminal domain of tetanus neurotoxin (Hc-TeNT). Computational simulations of a novel small cyclic oligopeptide are designed, synthesized, and tes...
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MDPI AG
2021-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/13/3988 |
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| author | Ana Candalija Thomas Scior Hans-Richard Rackwitz Jordan E. Ruiz-Castelan Ygnacio Martinez-Laguna José Aguilera |
| author_facet | Ana Candalija Thomas Scior Hans-Richard Rackwitz Jordan E. Ruiz-Castelan Ygnacio Martinez-Laguna José Aguilera |
| author_sort | Ana Candalija |
| collection | DOAJ |
| description | This article presents experimental evidence and computed molecular models of a potential interaction between receptor domain D5 of TrkB with the carboxyl-terminal domain of tetanus neurotoxin (Hc-TeNT). Computational simulations of a novel small cyclic oligopeptide are designed, synthesized, and tested for possible tetanus neurotoxin-D5 interaction. A hot spot of this protein-protein interaction is identified in analogy to the hitherto known crystal structures of the complex between neurotrophin and D5. Hc-TeNT activates the neurotrophin receptors, as well as its downstream signaling pathways, inducing neuroprotection in different stress cellular models. Based on these premises, we propose the Trk receptor family as potential proteic affinity receptors for TeNT. In vitro, Hc-TeNT binds to a synthetic TrkB-derived peptide and acts similar to an agonist ligand for TrkB, resulting in phosphorylation of the receptor. These properties are weakened by the mutagenesis of three residues of the predicted interaction region in Hc-TeNT. It also competes with Brain-derived neurotrophic factor, a native binder to human TrkB, for the binding to neural membranes, and for uptake in TrkB-positive vesicles. In addition, both molecules are located together in vivo at neuromuscular junctions and in motor neurons. |
| first_indexed | 2024-03-10T09:56:41Z |
| format | Article |
| id | doaj.art-5c5c500ec74f4522ad53b120491fe19a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T09:56:41Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-5c5c500ec74f4522ad53b120491fe19a2023-11-22T02:18:47ZengMDPI AGMolecules1420-30492021-06-012613398810.3390/molecules26133988Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus NeurotoxinAna Candalija0Thomas Scior1Hans-Richard Rackwitz2Jordan E. Ruiz-Castelan3Ygnacio Martinez-Laguna4José Aguilera5Molecular Biology Department, Institut de Neruociènces and Biochemistry, Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, SpainFaculty of Chemical Sciences, BUAP, Puebla 72000, MexicoPeptide Specialities Laboratory, Im Neuenheimer Feld, Univerisity Campus, 69120 Heidelberg, GermanyFaculty of Chemical Sciences, BUAP, Puebla 72000, MexicoFaculty of Chemical Sciences, BUAP, Puebla 72000, MexicoMolecular Biology Department, Institut de Neruociènces and Biochemistry, Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, SpainThis article presents experimental evidence and computed molecular models of a potential interaction between receptor domain D5 of TrkB with the carboxyl-terminal domain of tetanus neurotoxin (Hc-TeNT). Computational simulations of a novel small cyclic oligopeptide are designed, synthesized, and tested for possible tetanus neurotoxin-D5 interaction. A hot spot of this protein-protein interaction is identified in analogy to the hitherto known crystal structures of the complex between neurotrophin and D5. Hc-TeNT activates the neurotrophin receptors, as well as its downstream signaling pathways, inducing neuroprotection in different stress cellular models. Based on these premises, we propose the Trk receptor family as potential proteic affinity receptors for TeNT. In vitro, Hc-TeNT binds to a synthetic TrkB-derived peptide and acts similar to an agonist ligand for TrkB, resulting in phosphorylation of the receptor. These properties are weakened by the mutagenesis of three residues of the predicted interaction region in Hc-TeNT. It also competes with Brain-derived neurotrophic factor, a native binder to human TrkB, for the binding to neural membranes, and for uptake in TrkB-positive vesicles. In addition, both molecules are located together in vivo at neuromuscular junctions and in motor neurons.https://www.mdpi.com/1420-3049/26/13/3988clostridium neurotoxinsneurotrophin receptorscarboxyl-terminal domain of tetanus neurotoxinbrain-derived neurotrophic factor |
| spellingShingle | Ana Candalija Thomas Scior Hans-Richard Rackwitz Jordan E. Ruiz-Castelan Ygnacio Martinez-Laguna José Aguilera Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin Molecules clostridium neurotoxins neurotrophin receptors carboxyl-terminal domain of tetanus neurotoxin brain-derived neurotrophic factor |
| title | Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin |
| title_full | Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin |
| title_fullStr | Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin |
| title_full_unstemmed | Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin |
| title_short | Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin |
| title_sort | interaction between a novel oligopeptide fragment of the human neurotrophin receptor trkb ectodomain d5 and the c terminal fragment of tetanus neurotoxin |
| topic | clostridium neurotoxins neurotrophin receptors carboxyl-terminal domain of tetanus neurotoxin brain-derived neurotrophic factor |
| url | https://www.mdpi.com/1420-3049/26/13/3988 |
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