A lipid-binding loop of botulinum neurotoxin serotypes B, DC and G is an essential feature to confer their exquisite potency
| Autor: | Laura von Berg, Peter B. Luppa, Jasmin Weisemann, Andreas Rummel, Michael Laue, Martin B. Dorner, Janett Piesker, Brigitte G. Dorner, Daniel Stern, Stefan Mahrhold, Alexander Le Blanc |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Botulinum Toxins Protein Conformation Plasma protein binding Toxicology Pathology and Laboratory Medicine Crystallography X-Ray Biochemistry Binding Analysis Mice Protein structure Gangliosides Medicine and Health Sciences Toxins Neurotransmitter metabolism Botulinum Toxins Type A Receptor lcsh:QH301-705.5 Membrane Glycoproteins Chemistry Physics Chromatographic Techniques Lipids Receptors Neurotransmitter Amino Acid Specific Chromatography Physical Sciences Thermodynamics Synaptic Vesicles Hydrophobic and Hydrophilic Interactions Research Article Protein Binding lcsh:Immunologic diseases. Allergy Immunology Toxic Agents Bacterial Toxins Botulinum Toxin Research and Analysis Methods Serogroup Microbiology Synaptic vesicle Synaptotagmin 1 03 medical and health sciences Virology Genetics Glutathione Chromatography Animals ddc:610 Binding site Protein Interactions Molecular Biology Protein-Lipid Interactions Chemical Characterization Sphingolipids Ganglioside Binding Sites Toxicity Affinity Chromatography Cell Membrane Biology and Life Sciences Proteins 030104 developmental biology lcsh:Biology (General) Biophysics Parasitology Carrier Proteins lcsh:RC581-607 610 Medizin und Gesundheit |
| Zdroj: | PLoS Pathogens, Vol 14, Iss 5, p e1007048 (2018) PLoS Pathogens |
| DOI: | 10.25646/5679 |
| Popis: | The exceptional toxicity of botulinum neurotoxins (BoNTs) is mediated by high avidity binding to complex polysialogangliosides and intraluminal segments of synaptic vesicle proteins embedded in the presynaptic membrane. One peculiarity is an exposed hydrophobic loop in the toxin’s cell binding domain HC, which is located between the ganglioside- and protein receptor-binding sites, and that is particularly pronounced in the serotypes BoNT/B, DC, and G sharing synaptotagmin as protein receptor. Here, we provide evidence that this HC loop is a critical component of their tripartite receptor recognition complex. Binding to nanodisc-embedded receptors and toxicity were virtually abolished in BoNT mutants lacking residues at the tip of the HC loop. Surface plasmon resonance experiments revealed that only insertion of the HC loop into the lipid-bilayer compensates for the entropic penalty inflicted by the dual-receptor binding. Our results represent a new paradigm of how BoNT/B, DC, and G employ ternary interactions with a protein, ganglioside, and lipids to mediate their extraordinary neurotoxicity. Author summary Botulinum neurotoxins are Janus-faced molecules: due to their exquisite toxicity, botulinum neurotoxins are considered as biological weapons, but they are also highly effective medicines for numerous neurological indications. However, what mediates their exquisite toxicity? The exclusive binding to neurons and the subsequent paralysis cuts off the host’s communication networks. The neurospecific binding is ensured by anchoring to two receptor molecules both embedded in the membrane: a complex ganglioside and a synaptic vesicle protein. Here, we reveal a third interaction between a hydrophobic so-called HC loop protruding from the surface of the serotypes BoNT/B, DC, and G into the lipid membrane. Only this HC loop ensures their high-affinity binding to the neuronal receptors also at physiological temperature (37°C). Hereby, BoNT/B, DC, and G prevent untimely dissociation prior to uptake into the neuron. Therefore, our study provides the mechanistic basis for the development of inhibitors to combat botulism, but it also has implications for engineering toxin—membrane interactions yielding optimized BoNT-based therapeutics to treat neuromuscular dysfunctions successfully. Intriguingly, a broadly neutralizing anti-HIV-1 antibody shares a similar strategy, emphasizing the general relevance of our results for host—pathogen interactions. |
| Databáze: | OpenAIRE |
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