title: Receptor binding enables botulinum neurotoxin B to sense low pH for translocation channel assembly.
abstract: Botulinum neurotoxins (BoNTs, serotypes A-G), elaborated by Clostridium botulinum, can induce lethal paralysis and are classified as Category A bioterrorism agents. However, how BoNTs translocate from endosomes into the cytosol of neurons to gain access to their intracellular targets remains enigmatic. We discovered that binding to the ganglioside GT1b, a toxin coreceptor, enables BoNT/B to sense low pH, undergo a significant change in secondary structure, and transform into a hydrophobic oligomeric membrane protein. Imaging of the toxin on lipid bilayers using atomic force microscopy revealed donut-shaped channel-like structures that resemble other protein translocation assemblies. Toosendanin, a drug with therapeutic effects against botulism, inhibited GT1b-dependent BoNT/B oligomerization and in parallel truncated BoNT/B single-channel conductance, suggesting that oligomerization plays a role in the translocation reaction. Thus, BoNT/B functions as a coincidence detector for receptor and low pH to ensure spatial and temporal accuracy for toxin conversion into a translocation channel.
authors.affiliation: Howard Hughes Medical Institute, USA.
authors.forename: Shihu
authors.initials: S
authors.lastname: Sun
authors.forename: Swetha
authors.initials: S
authors.lastname: Suresh
authors.forename: Huisheng
authors.initials: H
authors.lastname: Liu
authors.forename: William H
authors.initials: WH
authors.lastname: Tepp
authors.forename: Eric A
authors.initials: EA
authors.lastname: Johnson
authors.forename: J Michael
authors.initials: JM
authors.lastname: Edwardson
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chapman
mesh_terms: D000818:Animals; D001665:Binding Sites; D001905:Botulinum Toxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019274:Botulinum Toxins, Type A; D001906:Botulism / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D002462:Cell Membrane / Q000378:metabolism / Q000382:microbiology; D003014:Clostridium botulinum / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
chemical_list: D005732:Gangliosides; D011956:Receptors, Cell Surface; C096323:rimabotulinumtoxinB; C016481:trisialoganglioside GT1; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A