A5016650829- Botulinum Toxin and Related Neurological Disorders
- Neurological disorders and treatments
- Cellular transport and secretion
- Hereditary Neurological Disorders
- Biochemical and Structural Characterization
- Toxin Mechanisms and Immunotoxins
- Lipid Membrane Structure and Behavior
- Genetic Neurodegenerative Diseases
- Cancer Treatment and Pharmacology
- Virology and Viral Diseases
- Boron Compounds in Chemistry
- Nerve injury and regeneration
- Streptococcal Infections and Treatments
- Forest Insect Ecology and Management
- Peptidase Inhibition and Analysis
- Animal Virus Infections Studies
- Clostridium difficile and Clostridium perfringens research
- Parkinson's Disease Mechanisms and Treatments
- Pancreatic function and diabetes
- RNA Interference and Gene Delivery
- Venomous Animal Envenomation and Studies
- Plant-based Medicinal Research
- Receptor Mechanisms and Signaling
- Boron and Carbon Nanomaterials Research
- Sympathectomy and Hyperhidrosis Treatments
Medizinische Hochschule Hannover
2016-2025
Federal Department of Home Affairs
2018
Howard Hughes Medical Institute
1993-2007
Stanford Synchrotron Radiation Lightsource
2007
Stanford University
2007
Brookhaven National Laboratory
2004-2005
Tetra Tech (United States)
2005
Hochschule Hannover
2005
Max Planck Institute for Biophysical Chemistry
2002
Saarland University
2002
Clostridial neurotoxins, tetanus toxin (TeTx) and the seven related but serologically distinct botulinal neurotoxins (BoNT/A to BoNT/G), are potent inhibitors of synaptic vesicle exocytosis in nerve endings. Recently it was reported that light chains clostridial act as zinc-dependent metalloproteases which specifically cleave target proteins such synaptobrevin/VAMPs, HPC-1/syntaxin (BoNT/C1), SNAP-25 (BoNT/A). We show here BoNT/E, like BoNT/A, cleaves SNAP-25, generated by vitro translation...
Tetanus toxin is a potent neurotoxin that inhibits the release of neurotransmitters from presynaptic nerve endings. The mature composed heavy and light chain are linked via disulfide bridge. After entry tetanus into cytoplasm, released causes block neurotransmitter release. Recent evidence suggests L-chain may act as metalloendoprotease. Here we demonstrate blockade neurotransmission by in isolated terminals associated with selective proteolysis synaptobrevin, an integral membrane protein...
Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by selectively cleaving core components of the vesicular fusion machinery. The synaptic vesicle proteins Synaptotagmin‐I and ‐II act as receptors for BoNT/B BoNT/G. Here we show that BoNT/A also interacts with a protein, glycoprotein 2C (SV2C), but not homologous SV2A SV2B. Binding occurs at membrane juxtaposed region preceding transmembrane domain 8. A peptide comprising intravesicular between domains 7 8 specifically reduces...
Tetanus toxin (TeTx) and the various forms of botulinal neurotoxins (BoNT/A to BoNT/G) potently inhibit neurotransmission by means their L chains which selectively proteolyze synaptic proteins such as synaptobrevin (TeTx, BoNT/B, BoNT/F), SNAP-25 (BoNT/A), syntaxin (BoNT/C1). Here we show that BoNT/D cleaves rat 1 2 in toxified synaptosomes isolated vesicles. In contrast, 1, generated vitro translation, is only a poor substrate for BoNT/D, whereas this species cleaved BoNT/F with similar...
Botulinum neurotoxins (BoNTs) induce muscle paralysis by selectively entering cholinergic motoneurons and subsequent specific cleavage of core components the vesicular fusion machinery. Complex gangliosides are requisite for efficient binding to neuronal cells, but protein receptors critical internalization. Recent work evidenced that synaptotagmins I II can function as BoNT/B (Dong, M., Richards, D. A., Goodnough, M. C., Tepp, W. H., Johnson, E. Chapman, R. (2003) J. Cell Biol. 162,...
The seven serologically different botulinum neurotoxins are highly potent protein toxins that inhibit neurotransmitter release from peripheral cholinergic synapses. activated consist of the toxifying A-subunits (Mr approximately 50,000) linked by a disulfide bond to receptor-binding BC-subunits 100,000). We have established complete sequence neurotoxin type A (BoNT/A; 1,296 amino acid residues, Mr = 149,425) and partial E (273 residues) as deduced corresponding nucleotide sequences...
Cellubrevin is a member of the synaptobrevin/VAMP family SNAREs, which has broad tissue distribution. In fibroblastic cells it concentrated in vesicles recycle transferrin receptors but its role membrane trafficking and fusion remains to be demonstrated. Cellubrevin, like synaptic vesicle proteins synaptobrevins I II, can cleaved by tetanus toxin, metallo-endoprotease blocks neurotransmitter release. However, nonneuronal are unaffected toxin due lack cell surface for heavy chain. To...
Tetanus and botulinum neurotoxins selectively invade neurons following binding to complex gangliosides. Recent biochemical experiments demonstrate that two ganglioside sites within the tetanus neurotoxin HC-fragment, originally identified in crystallographic studies bind lactose or sialic acid, are required for productive target cells. Here, we determine by mass spectroscopy HC-fragment of A B only one molecule GT1b. Mutations made presumed site abolished formation these...
Abstract : Tetanus toxin and the seven serologically distinct botulinal neurotoxins (BoNT/A to BoNT/G) abrogate synaptic transmission at nerve endings through action of their light chains (L chains), which proteolytically cleave VAMP (vesicle‐associated membrane protein)/synaptobrevin, SNAP‐25 (synaptosome‐associated protein 25 kDa), or syntaxin. BoNT/C was reported proteolyze both syntaxin SNAP‐25. Here, we demonstrate that cleavage occurs between Arg 198 Ala 199 , depends on presence...
Botulinum neurotoxins (BoNTs) cause muscle paralysis by selectively cleaving core components of the vesicular fusion machinery within motoneurons. Complex gangliosides initially bind into a pocket that is conserved among seven BoNTs and tetanus neurotoxin. Productive neurotoxin uptake also requires protein receptors. The interaction site receptor currently unknown. We report identification characterization binding BoNT/B BoNT/G. Their receptors, synaptotagmins I II, to at tip their H(CC)...
The high toxicity of clostridial neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven botulinum neurotoxin serotypes A-G (BoNT/A-G) inhibit acetylcholine release, leading to flaccid paralysis, while tetanus blocks neurotransmitter release in inhibitory resulting spastic paralysis. Uptake BoNT/A, B, E G requires a dual interaction with gangliosides synaptic vesicle (SV) proteins synaptotagmin or SV2, whereas little is known about entry...
Botulinum neurotoxins consist of a metalloprotease linked via conserved interchain disulfide bond to heavy chain responsible for neurospecific binding and translocation the enzymatic domain in nerve terminal cytosol. The activity is enabled upon reduction causes neuroparalysis by cleaving SNARE proteins. Here, we show that thioredoxin reductase-thioredoxin protein disulfide-reducing system present on synaptic vesicles it functional botulinum neurotoxin serotypes A, C, E. Specific inhibitors...
Abstract The genome of Weissella oryzae SG25T was recently sequenced and a botulinum neurotoxin (BoNT) like gene identified by bioinformatics methods. typical three-domains organization BoNTs with N-terminal metalloprotease domain, translocation cell binding domains could be identified. BoNT family neurotoxins is rapidly growing, but this the first indication possible expression toxin outside Clostridium genus. We performed molecular modeling dynamics simulations showing that 50 kDa domain...
Activation of protein kinase C (PKC) constitutes a key event in the upregulation secretory strength neurons and neurosecretory cells during extensive stimulation, presumably by speeding up vesicle supply. However, molecular targets their mode action remain elusive. We studied only PKC-dependent phosphorylation site neuronal soluble<i>N</i>-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex, Ser<sup>187</sup>, synaptosome-associated 25 kDa (SNAP-25). This is located within...