eprintid: 10194345 rev_number: 9 eprint_status: archive userid: 699 dir: disk0/10/19/43/45 datestamp: 2024-07-10 09:50:47 lastmod: 2024-07-10 09:50:47 status_changed: 2024-07-10 09:50:47 type: article metadata_visibility: show sword_depositor: 699 creators_name: Surana, Sunaina creators_name: Villarroel Campos, David creators_name: Rhymes, Ellie R creators_name: Kalyukina, Maria creators_name: Panzi, Chiara creators_name: Novoselov, Sergey S creators_name: Fabris, Federico creators_name: Richter, Sandy creators_name: Pirazzini, Marco creators_name: Zanotti, Giuseppe creators_name: Sleigh, James N creators_name: Schiavo, Giampietro title: The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex ispublished: inpress divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F85 keywords: LAR, Neuromuscular Junction, Nidogen, PTPRD, Tetanus neurotoxin note: © 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible. abstract: Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. It binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. Whilst the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear. Here, we show that the receptor-type protein tyrosine phosphatases LAR and PTPRD interact with the nidogen-TeNT complex, enabling its neuronal uptake. Binding of LAR and PTPRD to the toxin complex is mediated by their immunoglobulin and fibronectin III domains, which we harnessed to inhibit TeNT entry into motor neurons and protect mice from TeNT-induced paralysis. This function of LAR is independent of its role in regulating TrkB receptor activity, which augments axonal transport of TeNT. These findings reveal a multi-subunit receptor complex for TeNT and demonstrate a novel trafficking route for extracellular matrix proteins. Importantly, this paves the way for developing therapeutics to prevent tetanus and dissecting the mechanisms controlling the targeting of physiological ligands to long-distance axonal transport in the nervous system. date: 2024-07-08 date_type: published official_url: https://doi.org/10.1038/s44318-024-00164-8 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2293067 doi: 10.1038/s44318-024-00164-8 lyricists_name: Surana, Sunaina lyricists_id: SSURA08 actors_name: Surana, Sunaina actors_id: SSURA08 actors_role: owner funding_acknowledgements: LT000220/2017-L [Human Frontier Science Program]; MR/S006990/1 [Medical Research Council]; MR/Y010949/1 [Medical Research Council]; MR/X502984/1 [Medical Research Council]; [The Sigrid Rausing Trust]; 107116/Z/15/Z [Wellcome Trust]; 223022/Z/21/Z [Wellcome Trust]; UKDRI-1005 [UK Dementia Research Institute]; 520 [Alzheimer's Society] full_text_status: public publication: The EMBO Journal issn: 0261-4189 citation: Surana, Sunaina; Villarroel Campos, David; Rhymes, Ellie R; Kalyukina, Maria; Panzi, Chiara; Novoselov, Sergey S; Fabris, Federico; ... Schiavo, Giampietro; + view all <#> Surana, Sunaina; Villarroel Campos, David; Rhymes, Ellie R; Kalyukina, Maria; Panzi, Chiara; Novoselov, Sergey S; Fabris, Federico; Richter, Sandy; Pirazzini, Marco; Zanotti, Giuseppe; Sleigh, James N; Schiavo, Giampietro; - view fewer <#> (2024) The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex. The EMBO Journal 10.1038/s44318-024-00164-8 <https://doi.org/10.1038/s44318-024-00164-8>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10194345/2/Surana_surana-et-al-2024-the-tyrosine-phosphatases-lar-and-ptpr%CE%B4-act-as-receptors-of-the-nidogen-tetanus-toxin-complex.pdf