Botulinum neurotoxin D-C uses synaptotagmin I/II as receptors and human synaptotagmin II is not an effective receptor for type B, D-C, and G toxins

Peng, Lisheng; Berntsson, R.P.-A.; Tepp, William H.; Pitkin, Rose M.; Johnson, Eric A.; Stenmark, Pål; Dong, Min

doi:10.1242/jcs.103564

Cited by 93 publications

(130 citation statements)

References 53 publications

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“…Taken together, these results provide proof in principle of the feasibility of engineering a toxin with an even longer duration than /A. Nevertheless, therapeutic application of this variant would require further research to circumvent the lowered affinity of the /B binding domain for its synaptotagmin II acceptor in humans [38,39].…”

Section: Insights Gained Into Devising Bont-based Neurotherapeutics Wmentioning

confidence: 65%

Engineering of botulinum neurotoxins as novel therapeutic tools

Dolly

Wang

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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Section: Insights Gained Into Devising Bont-based Neurotherapeutics Wmentioning

confidence: 65%

Engineering of botulinum neurotoxins as novel therapeutic tools

Dolly

Wang

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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“…However, its H CC domain is only 28 % identical to H CC B and H CC G but 61 % identical to H CC C which does not interact with any Syt isoform. That might be the reason for higher apparent dissociation constants of BoNT/DC for Syt-II than BoNT/B under similar assay conditions (330 versus 8.6 nM) [67].…”

Section: Synaptic Vesicle Proteins Are Receptors Of Bontsmentioning

confidence: 94%

“…An alternative, partially overlapping hydrophobic area was analysed. Mutations Y1180K, I1264Q and P1182S/S1183Y reduced the binding of both Syt-I and Syt-II, whereas L1196R and L1226K selectively diminished the binding of Syt-II without affecting Syt-I binding significantly [67]. In conclusion, Syt-I and Syt-II always adopt an α-helical structure of 14-17 residues to interact with the H CC domain of BoNT/B and G at homologous sites, whereas BoNT/DC binds Syt-I and Syt-II at a closely related site with a unique recognition motif.…”

Section: Mode Of the Bont-protein Receptor Interactionmentioning

confidence: 96%

“…Introducing the corresponding mutation F54 L into Syt-II of mouse or rat origin resulted in a complete loss of binding of BoNT/B, DC and G and cannot be rescued by the presence of gangliosides [67,119]. Interaction of BoNT/B with Syt-I, whose corresponding residue F46 is strictly conserved in all sequenced species, can only partially compensate this single mutation.…”

Section: Mode Of the Bont-protein Receptor Interactionmentioning

confidence: 99%

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The Dual-Receptor Recognition of Botulinum Neurotoxins

Rummel

2014

Molecular Aspects of Botulinum Neurotoxin

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The neurospecificity of the botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) is one important reason for their extraordinarily high toxicity. This neurospecific binding is mediated by the interaction with two receptor components. All BoNTs and TeNT bind first to complex polysialo-gangliosides abundantly present on the outer leaflet of neuronal membranes. The ganglioside binding occurs in BoNT/A, B, E, F, G and TeNT via a conserved ganglioside-binding pocket within the most carboxyl-terminal 25-kDa domain H CC , whereas BoNT/C and D display two different ganglioside-binding sites within this H CC domain. Subsequently, upon exocytosis, the intraluminal domains of synaptic vesicle proteins are exposed and can be accessed by the surface-accumulated neurotoxins. BoNT/B, DC and G bind with their H CC domain to a 15-17mer membrane-juxtaposed segment of the intraluminal domain of synaptotagmin-I and synaptotagmin-II, respectively. In contrast, the H C fragment of BoNT/A and E interacts via an extensive surface with the intraluminal domain 4 of the synaptic vesicle glycoprotein 2 (SV2). Whereas BoNT/A interacts with all three SV2 isoforms, BoNT/E only binds SV2A and SV2B. Also, BoNT/D, F and TeNT are supposed to employ SV2 for neurospecific uptake although a direct interaction has to be demonstrated. Thereafter, the synaptic vesicle is recycled and the bound neurotoxin is endocytosed. Acidification of the vesicle lumen triggers membrane insertion of the translocation domain while the protein receptor binding is maintained, pore formation and, finally, translocation of the enzymatically active light chain. Keywords

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“…The B domain (HC) contains a receptor binding domain (HC C ) and a translocation domain (HC N ). BoNTs bind dual neuronal receptors: a sialic acid-decorated glycolipid known as a ganglioside and a synaptic vesicle protein or a second ganglioside (14)(15)(16)(17)(18)(19)(20). BoNTs enter neurons via synaptic vesicles where HC N facilitates pH-dependent delivery of the catalytic A domain (light chain [LC]) into the cytosol (21).…”

Section: T His Commentary Addresses Studies By Mantis and Coworkers mentioning

confidence: 99%

Protein Structure Facilitates High-Resolution Immunological Mapping

Zuverink

Barbieri

2017

Clin Vaccine Immunol

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Select agents (SA) pose unique challenges for licensing vaccines and therapies. In the case of toxin-mediated diseases, HHS assigns guidelines for SA use, oversees vaccine and therapy development, and approves animal models and approaches to identify mechanisms for toxin neutralization. In this commentary, we discuss next-generation vaccines and therapies against ricin toxin and botulinum toxin, which are regulated SA toxins that utilize structure-based approaches for countermeasures to guide rapid response to future biothreats.KEYWORDS botulinum toxin, RTA, RVEc, RiVax, antibodies, mass spectrometry, ricin T his commentary addresses studies by Mantis and coworkers, who in this issue of Clinical and Vaccine Immunology describe the continued mapping of the neutralizing epitopes within ricin toxin (RTX) and relate these studies to current research on the botulinum neurotoxins (BoNTs) (1, 2). Our goal is to provide a perspective on how protein structure has facilitated development of vaccines and therapies against regulated select agent (SA) toxins. An overview of the properties of ricin toxin and botulinum neurotoxin is presented in Fig. 1. Ricin toxin and the botulinum neurotoxins are HHS and USDA Select Agents and Toxins (7 CFR part 331, 9 CFR part 121, and 42 CFR part 73).AB toxin structure/function. AB toxins contain modular domains with distinct functional activities (3). The A domain encodes an enzymatic activity which targets a host protein to modulate host cell physiology, often inactivating a biological process within cells, leading to cell death or occasionally enhancing the action of a cellular process. The B domain often binds a host receptor, such as a protein or glycolipid, via interactions that bind directly to a specific host receptor or that bind a carbohydrate present on a glycosylated host receptor. AB toxins are often synthesized as single-chain proteins in an inactive form and are converted to an active di-chain by proteolysis between the A and B domains, which remain connected by an interchain disulfide (4, 5).RTX is a category B bioterrorism toxigenic lectin enriched in seeds of the castor bean plant Ricinus communis. RTX is posttranslationally processed by host glycosylation and activated by cleavage between A and B domains (6, 7). The ricin toxin A domain (RTA) is a type II ribosome-inactivating protein with N-glycosidase activity, which depurinates 28S rRNA within the 60S host ribosome (8). Depurination stalls protein synthesis and induces a ribotoxic stress response (9). Ricin toxin B domain (RTB) contains at least two homologous lectin binding sites specific for galactose and binds galactose-containing lipids and glycoproteins (10). While binding of galactose results in nonproductive uptake of RTX, binding to mannose moieties on host mannose-containing receptors results in RTX retrograde trafficking to the endoplasmic reticulum, where RTA is delivered into the cytosol to target the ribosome (11). RTX exploits receptors on multiple cell types; therefore, the symptoms vary based ...

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Botulinum neurotoxin D-C uses synaptotagmin I/II as receptors and human synaptotagmin II is not an effective receptor for type B, D-C, and G toxins

Cited by 93 publications

References 53 publications

Engineering of botulinum neurotoxins as novel therapeutic tools

Engineering of botulinum neurotoxins as novel therapeutic tools

The Dual-Receptor Recognition of Botulinum Neurotoxins

Protein Structure Facilitates High-Resolution Immunological Mapping

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