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Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A)

Academic Article
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Overview

authors

  • Jacky, B. P. S.
  • Garay, P. E.
  • Dupuy, J.
  • Nelson, J. B.
  • Cai, B.
  • Molina, Y.
  • Wang, J.
  • Steward, L. E.
  • Broide, R. S.
  • Francis, J.
  • Aoki, K. R.
  • Stevens, Raymond
  • Fernandez-Salas, E.

publication date

  • May 2013

journal

  • PLoS Pathogens  Journal

abstract

  • Botulinum neurotoxin serotype A (BoNT/A) causes transient muscle paralysis by entering motor nerve terminals (MNTs) where it cleaves the SNARE protein Synaptosomal-associated protein 25 (SNAP25206) to yield SNAP25197. Cleavage of SNAP25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. The specific uptake of BoNT/A into pre-synaptic nerve terminals is a tightly controlled multistep process, involving a combination of high and low affinity receptors. Interestingly, the C-terminal binding domain region of BoNT/A, HC/A, is homologous to fibroblast growth factors (FGFs), making it a possible ligand for Fibroblast Growth Factor Receptors (FGFRs). Here we present data supporting the identification of Fibroblast Growth Factor Receptor 3 (FGFR3) as a high affinity receptor for BoNT/A in neuronal cells. HC/A binds with high affinity to the two extra-cellular loops of FGFR3 and acts similar to an agonist ligand for FGFR3, resulting in phosphorylation of the receptor. Native ligands for FGFR3; FGF1, FGF2, and FGF9 compete for binding to FGFR3 and block BoNT/A cellular uptake. These findings show that FGFR3 plays a pivotal role in the specific uptake of BoNT/A across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions.

subject areas

  • Animals
  • Botulinum Toxins, Type A
  • Cell Membrane
  • HEK293 Cells
  • Humans
  • Mice
  • PC12 Cells
  • Protein Transport
  • Rats
  • Receptor, Fibroblast Growth Factor, Type 3
  • Synaptosomal-Associated Protein 25
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Identity

PubMed Central ID

  • PMC3656097

International Standard Serial Number (ISSN)

  • 1553-7374

Digital Object Identifier (DOI)

  • 10.1371/journal.ppat.1003369

PubMed ID

  • 23696738
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Additional Document Info

start page

  • e1003369

volume

  • 9

issue

  • 5

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