1,721,348 research outputs found
The blockade of the neurotransmitter release apparatus by botulinum neurotoxins
No full textThe high toxicity of the seven serotypes of
botulinum neurotoxins (BoNT/A to G), together with their
specificity and reversibility, includes them in the list A
of potential bioterrorism weapons and, at the same time,
among the therapeutics of choice for a variety of human
syndromes. They invade nerve terminals and cleave specifically
the three proteins which form the heterotrimeric
SNAP REceptors (SNARE) complex that mediates neurotransmitter
release. The BoNT-induced cleavage of the
SNARE proteins explains by itself the paralysing activity
of the BoNTs because the truncated proteins cannot form
the SNARE complex. However, in the case of BoNT/A, the
most widely used toxin in therapy, additional factors come
into play as it only removes a few residues from the synaptosomal
associate protein of 25 kDa C-terminus and this
results in a long duration of action. To explain these facts
and other experimental data, we present here a model for
the assembly of the neuroexocytosis apparatus in which
Synaptotagmin and Complexin first assist the zippering of
the SNARE complex, and then stabilize and clamp an octameric
radial assembly of the SNARE complexes
Peculiar binding of botulinum neurotoxins
No full textBotulinum neurotoxin (BoNT) is a bacterial toxin that causes paralysis. Recent models have suggested that BoNT recognizes and enters nerve endings by interacting with protein receptors and gangliosides, which are glycosphingolipid components of the cell membrane that modulate cell signaling. Recent structures provide insight into how BoNT interacts with these cell surface components and open the door for the development of inhibitors against this neurotoxin
Where and how do anthrax toxins exit endosomes to intoxicate host cells?
No full textThe role of Bacillus anthracis virulence factors in its pathogenesis has been subjected to intense investigation with the aim of finding novel preventive and therapeutic protocols. Toxins that are endocytosed and act in the cytosol of host cells have a central role in B. anthracis infection. Understanding of anthrax toxin cell entry has increased during the past few years and a composite picture is emerging. Nevertheless, unanswered and controversial questions remain, particularly concerning the site and mode of anthrax toxin cell entry, the role of anthrax toxin receptors in the process and the possible involvement of cytosolic chaperones, which might affect entry efficiency. Here, the current model of anthrax toxin cell entry, an alternative model and experimental approaches for clarifying unanswered questions will be discussed. © 2007 Elsevier Ltd. All rights reserved
Botulinum neurotoxins: revival of an old killer.
No full textBotulinal neurotoxins (BoNTs) produced by anaerobic bacteria of the genus Clostridium are the most toxic proteins known, with mouse LD(50) values in the range of 1-5 ng/kg. They are responsible for the pathophysiology of botulism. BoNTs are metalloproteinases that enter peripheral cholinergic nerve terminals, where they cleave one or two of the three core proteins of the neuroexocytosis apparatus and elicit persistent but reversible inhibition of neurotransmitter release. Their specificity of action has made them useful therapeutic agents for many human syndromes caused by hyperactivity of cholinergic nerve terminals. Their range of clinical applications is continuously growing, and BoNT/A is being used extensively as a pharmaco-cosmetic
On the quaternary structure of taipoxin and textilotoxin: The advantage of being multiple
No full textMany presynaptic neurotoxins endowed with a phospholipase A2 activity are produced by a variety of snake species (Harris, 1991; Kini, 1997). These toxins have evolved from PLA2 enzymes mainly implicated in digestive functions (Davidson and Dennis, 1990). The evolutionary transition from a hydrolytic enzyme to a toxin has been achieved without significant modifications to the stable multi-disulfide-bridged protein PLA2 scaffold, apart from the loss of the so-called “pancreatic loop” (Alape-Girón et al., 1999; Kini, 1997). Rather, subsequent mutations have generated the ability of some of these toxins to bind and act at the presynaptic membrane of motoneurons end plates (Fletcher and Jiang, 1995). This evolution has been driven by a very strong selection pressure, as prey immobilisation greatly improves the extent of feeding and therefore the fitness of the toxin-producing species. The acquisition of neurospecific binding properties by mutation and selection is at the basis of the transformation of a generic PLA2 enzyme into a presynaptic neurotoxin as it concentrates their phospholipid hydrolytic activity within selected portions of the plasma membrane, whose alteration results in loss of neurotransmission (Kini and Evans, 1989; Fletcher and Jiang, 1995; Kini, 2003). The ensuing change of membrane structure and the increased permeability to Ca2+ causes a sustained blockade of the transmission of the nerve impulse to the muscle ( [Rigoni et al., 2005] and [Rigoni et al., 2007]; Rossetto and Montecucco, 2008)
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