title: Synchronized chaperone function of botulinum neurotoxin domains mediates light chain translocation into neurons.
abstract: Clostridium botulinum neurotoxin (BoNT) is a multidomain protein in which the individual modules work in synchronized cooperative action in order to enter into neurons and inhibit synaptic transmission. The di-chain protein is made up of the ~50 kD light chain and the ~100 kD heavy chain. The HC can be further subdivided into the N-terminal translocation domain (H(N)) and the C-terminal Receptor Binding Domain (H(C)). BoNT entry into neurons requires the toxin to utilize the host cell's endocytosis pathway where it exploits the acidic environment of the endosome. Within the endosome the H(C) triggers the H(N) to change conformation from a soluble protein to a membrane inserted protein-conducting channel in precise timing with LC refolding. The LC must partially unfold to a translocation competent conformation in order to be translocated by the H(N) channel in an N to C terminal direction. Upon completion of translocation, the LC is released from the HC and allowed to interact with its substrate SNARE protein. This article discusses the individual functions of each module as well as the mechanisms by which each domain serves as a chaperone for the others, working in concert to achieve productive intoxication.
authors.affiliation: Asymmetric Operations Department, Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA. Audrey.Fischer@jhuapl.edu
authors.forename: Audrey
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000378:metabolism*; D001906:Botulism / Q000378:metabolism / Q000382:microbiology; D002462:Cell Membrane / Q000378:metabolism; D003014:Clostridium botulinum / Q000378:metabolism / Q000472:pathogenicity; D003600:Cytosol / Q000378:metabolism; D055724:Electrophysiological Phenomena; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D009498:Neurotoxins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D058767:Protein Unfolding; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology; D050600:SNARE Proteins / Q000378:metabolism
chemical_list: D007473:Ion Channels; D008051:Lipid Bilayers; D018832:Molecular Chaperones; D009498:Neurotoxins; D011956:Receptors, Cell Surface; D050600:SNARE Proteins; C034993:ganglioside receptor; D001905:Botulinum Toxins