A5078313223- Cellular transport and secretion
- Botulinum Toxin and Related Neurological Disorders
- Lipid Membrane Structure and Behavior
- Neurological disorders and treatments
- Biochemical and Structural Characterization
- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Pain Mechanisms and Treatments
- Hereditary Neurological Disorders
- Parkinson's Disease Mechanisms and Treatments
- Migraine and Headache Studies
- Sphingolipid Metabolism and Signaling
- Retinal Development and Disorders
- Receptor Mechanisms and Signaling
- Erythrocyte Function and Pathophysiology
- Monoclonal and Polyclonal Antibodies Research
- Venomous Animal Envenomation and Studies
- Cancer Treatment and Pharmacology
- Cell death mechanisms and regulation
- RNA Interference and Gene Delivery
- Nerve injury and regeneration
- Lysosomal Storage Disorders Research
- Signaling Pathways in Disease
- Toxin Mechanisms and Immunotoxins
- Biotin and Related Studies
University of Sheffield
2015-2024
MRC Laboratory of Molecular Biology
2005-2014
University of Vermont
2014
Medical Research Council
1998-2012
University of Cambridge
2004-2012
Wellcome Trust
2007
RELX Group (United Kingdom)
2005
Imperial College London
1996-2000
Howard Hughes Medical Institute
1993-1996
The University of Texas Southwestern Medical Center
1993-1996
Synaptotagmin I is a Ca(2+)- and phospholipid-binding protein of synaptic vesicles with an essential function in neurotransmission. Ca2+/phospholipid binding by synaptotagmin may be mediated its C2 domains, sequence motifs that have been implicated the Ca2+ regulation variety proteins. However, it currently unknown if domains are sufficient for or they even directly participate binding. In order to address this question, we studied Ca2+/phospholipid-binding properties first domain I. Our...
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...
C2 domains are found in many proteins involved membrane traffic or signal transduction. Although thought to bind calcium ions, the structural basis for binding is unclear. Analysis of synaptotagmin I and protein kinase C-beta by nuclear magnetic resonance spectroscopy revealed a bipartite calcium-binding motif that involves coordination two ions five aspartate residues located on separate loops. Sequence comparisons indicated this may be widely used motif, designated here as motif.
α-Latrotoxin (LTX) stimulates massive exocytosis of synaptic vesicles and may help to elucidate the mechanism regulation neurosecretion. We have recently isolated latrophilin, Ca2+-independent LTX receptor. Now we demonstrate that latrophilin is a novel member secretin family G protein-coupled receptors are involved in secretion. Northern blot analysis shows message present only neuronal tissue. Upon expression COS cells, cloned protein indistinguishable from brain binds with high affinity....
Missense mutations (A30P and A53T) in alpha-synuclein the overproduction of wild-type protein cause familial forms Parkinson's disease dementia with Lewy bodies. Alpha-synuclein is major component filamentous bodies neurites that define these diseases at a neuropathological level. Recently, third missense mutation (E46K) was described an inherited form Here, we have investigated functional effects this novel on phospholipid binding filament assembly alpha-synuclein. When compared to protein,...
Botulinum neurotoxin type A (BoNT/A) is a highly potent that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests neurotoxic activity BoNT/A not restricted to periphery, but also reaches CNS after retrograde axonal transport. Because internalized recycling synaptic vesicles, it unclear which compartment facilitates this Using live-cell confocal and single-molecule imaging rat hippocampal neurons...
Ca2+-dependent neurotransmitter release consists of at least two components: a major fast component that is insensitive to Sr2+ and minor slow potentiated by (Goda, Y., Stevens, C. F.(1994) Proc. Natl. Acad. U. S. A. 91, 12942-12946). These results suggest Ca2+ sensors act in synaptic vesicle fusion with distinct binding properties. We have now investigated the relative activities synaptotagmins evaluate their potential roles as for components. Our demonstrate first C2 domains I, II, III, V,...
Synaptotagmins are membrane proteins that possess tandem C2 domains and play an important role in regulated fusion metazoan organisms. Here we show both synaptotagmins I II, the two major neuronal isoforms, can interact with syntaxin/synaptosomal-associated protein of 25 kDa (SNAP-25) dimer, immediate precursor soluble NSF attachment receptor (SNARE) complex. A stretch basic amino acids highly conserved throughout animal kingdom is responsible for this calcium-independent interaction....
SNARE complex assembly constitutes a key step in exocytosis that is rendered Ca 2+ -dependent by interactions with synaptotagmin-1. Two putative sites for synaptotagmin binding have recently been identified SNAP-25 using biochemical methods: one located around the center and another at C-terminal end of bundle. However, it still unclear whether how synaptotagmin-1 × these are involved regulating fast neurotransmitter release. Here, we used electrophysiological techniques high time-resolution...
Chronic pain presents an enormous personal and economic burden there is urgent need for effective treatments. In a mouse model of chronic neuropathic pain, selective silencing key neurons in spinal signalling networks with botulinum constructs resulted reduction behaviours associated the peripheral nerve. However, to establish clinical relevance it was important know how long this period lasted. Now, we show that neuronal concomitant mechanical thermal hypersensitivity lasts up 120d...