title: Translocation of botulinum neurotoxin light chain protease through the heavy chain channel.
abstract: Clostridial botulinum neurotoxins (BoNTs) abort the process of neurotransmitter release at presynaptic motor nerve terminals, causing muscle paralysis. An enigmatic step in the intoxication process is the mechanism by which the neurotoxin heavy chain (HC) forms the conduit for the translocation of the light chain (LC) protease across the endosomal membrane into the cytosol, its site of action. Here we investigate the mechanism of LC translocation by using the combined detection of channel currents and substrate proteolysis, the two hallmark activities of BoNT. Our data are consistent with the translocation of the LC through the HC channel and show that the LC protease activity is retrieved in the trans compartment after translocation. We propose that the BoNT HC-LC complex embedded in the membrane is a transmembrane chaperone, a dynamic structural device that prevents aggregation and achieves translocation of the LC. In this regard, the complex is similar to the protein conducting/translocating channels of the endoplasmic reticulum, mitochondria and chloroplasts.
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0366, USA.
authors.forename: Lilia K
authors.initials: LK
authors.lastname: Koriazova
authors.forename: Mauricio
authors.initials: M
authors.lastname: Montal
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D007473:Ion Channels / Q000502:physiology; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology
chemical_list: D007473:Ion Channels; D009498:Neurotoxins; D010447:Peptide Hydrolases; D001905:Botulinum Toxins