Identification of the receptor-binding sites in the carboxyl-terminal half of the heavy chain of botulinum neurotoxin types C and D

Tsukamoto, Kentaro; Kozai, Yuiko; Ihara, Hideshi; Kohda, Tomoko; Mukamoto, Masafumi; Tsuji, Takao; Kozaki, Shunji

doi:10.1016/j.micpath.2007.12.003

Cited by 36 publications

(37 citation statements)

References 39 publications

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“…In the structure-based alignment, HCR/C and HCR/D-SA possess a homologous W within the GBL. Tsukamoto and colleagues reported that mutation of the W1258 to A reduced the ability of the HCR to compete with BoNT/C for synaptosome binding (42); here we show that this W contributes to ganglioside binding.…”

Section: Discussionsupporting

confidence: 65%

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Identification of a Unique Ganglioside Binding Loop within Botulinum Neurotoxins C and D-SA,

Karalewitz¹,

Kroken²,

Fu³

et al. 2010

Biochemistry

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The botulinum neurotoxins (BoNTs) are the most potent protein toxins for humans. There are seven serotypes of BoNTs (A-G) based on a lack of cross anti-sera neutralization. BoNTs utilize gangliosides as components of the host receptors for binding and entry into neurons. Members of BoNT/C and BoNT/D serotypes include mosaic toxins that are organized in D/C and C/D toxins. One D/C mosaic toxin, BoNT/D-South Africa (BoNT/D-SA), was not fully neutralized by immunization with BoNT serotype /C or /D, which stimulated this study. Here the crystal structures of the receptor binding domains of BoNT/C, BoNT/D, and BoNT/D-SA are presented. Biochemical and cell binding studies show that BoNT/C and BoNT/D-SA possess unique mechanisms for ganglioside binding. These studies provide new information on how the BoNTs can enter host cells as well as a basis for understanding the immunological diversity of these neurotoxins.

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Section: Discussionsupporting

confidence: 65%

“…Previous studies showed that HCR/C utilized W1258 for cell binding (42). Gangliosides were immobilized on a 96-well plate and HCRs and the mutated HCRs were tested for ganglioside binding affinity.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Unique Ganglioside Binding Loop within Botulinum Neurotoxins C and D-SA,

Karalewitz¹,

Kroken²,

Fu³

et al. 2010

Biochemistry

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“…Further analysis has identified a ␤-hairpin loop that contained a Trp residue with HCR/C, HCR/D, and HCR/D-C South Africa. This ␤-hairpin loop, which aligns near the SRS and is required for ganglioside and neuron binding, is termed the ganglioside binding loop (GBL) (3,30). Additional studies have expanded our understanding of how BoNT/C and BoNT/D bind cells.…”

mentioning

confidence: 99%

Botulinum Neurotoxin Serotype C Associates with Dual Ganglioside Receptors to Facilitate Cell Entry

Karalewitz

Baldwin

et al. 2012

Journal of Biological Chemistry

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“…In contrast, the conserved ganglioside-binding site is not present in the BoNT/C H C structure [25,88] (Fig. 6.1c), albeit the mutation of W1258 in BoNT/C, which aligns in the similar motif GXWY, clearly reduced the binding to gangliosides in synaptosomal membranes as well as biological activity [47,113]. W1258 is a part of a long loop extending out of the core structure of H CC C and therefore also termed the ganglioside-binding loop (GBL).…”

Section: The Mode Of Molecular Cnt-ganglioside Interactionmentioning

confidence: 99%

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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Identification of the receptor-binding sites in the carboxyl-terminal half of the heavy chain of botulinum neurotoxin types C and D

Cited by 36 publications

References 39 publications

Identification of a Unique Ganglioside Binding Loop within Botulinum Neurotoxins C and D-SA,

Identification of a Unique Ganglioside Binding Loop within Botulinum Neurotoxins C and D-SA,

Botulinum Neurotoxin Serotype C Associates with Dual Ganglioside Receptors to Facilitate Cell Entry

The Dual-Receptor Recognition of Botulinum Neurotoxins

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