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