title: Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A).
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.
authors.affiliation: Allergan, Department of Biological Sciences, Irvine, California, United States of America.
authors.forename: Birgitte P S
authors.initials: BP
authors.lastname: Jacky
authors.forename: Patton E
authors.initials: PE
authors.lastname: Garay
authors.forename: Jérôme
authors.initials: J
authors.lastname: Dupuy
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Nelson
authors.forename: Brian
authors.initials: B
authors.lastname: Cai
authors.forename: Yanira
authors.initials: Y
authors.lastname: Molina
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
authors.forename: Lance E
authors.initials: LE
authors.lastname: Steward
authors.forename: Ron S
authors.initials: RS
authors.lastname: Broide
authors.forename: Joseph
authors.initials: J
authors.lastname: Francis
authors.forename: K Roger
authors.initials: KR
authors.lastname: Aoki
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Ester
authors.initials: E
authors.lastname: Fernández-Salas
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016716:PC12 Cells; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism
chemical_list: C494208:SNAP25 protein, human; C494209:Snap25 protein, mouse; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; C069820:Fgfr3 protein, rat; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019274:Botulinum Toxins, Type A