title: On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments.
abstract: Tetanus and botulinum neurotoxins are produced by anaerobic bacteria of the genus Clostridium and are the most poisonous toxins known, with 50% mouse lethal dose comprised within the range of 0.1-few nanograms per Kg, depending on the individual toxin. Botulinum neurotoxins are similarly toxic to humans and can therefore be considered for potential use in bioterrorism. At the same time, their neurospecificity and reversibility of action make them excellent therapeutics for a growing and heterogeneous number of human diseases that are characterized by a hyperactivity of peripheral nerve terminals. The complete crystallographic structure is available for some botulinum toxins, and reveals that they consist of four domains functionally related to the four steps of their mechanism of neuron intoxication: 1) binding to specific receptors of the presynaptic membrane; 2) internalization via endocytic vesicles; 3) translocation across the membrane of endocytic vesicles into the neuronal cytosol; 4) catalytic activity of the enzymatic moiety directed towards the SNARE proteins. Despite the many advances in understanding the structure-mechanism relationship of tetanus and botulinum neurotoxins, the molecular events involved in the translocation step have been only partially elucidated. Here we will review recent advances that have provided relevant insights on the process and discuss possible models that can be experimentally tested. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy.
authors: Marco
authors: M
authors: Pirazzini
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy.
authors: Domenico
authors: D
authors: Azarnia Tehran
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy.
authors: Oneda
authors: O
authors: Leka
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy.
authors: Giulia
authors: G
authors: Zanetti
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy.
authors: Ornella
authors: O
authors: Rossetto
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy; Istituto CNR di Neuroscienze, Università di Padova, Via U. Bassi 58/B, 35121 Padova, Italy. Electronic address: cesare.montecucco@gmail.com.
authors: Cesare
authors: C
authors: Montecucco
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D017729:Presynaptic Terminals / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D050600:SNARE Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013744:Tetanus Toxin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050600:SNARE Proteins; D013744:Tetanus Toxin; D001905:Botulinum Toxins
keywords: Botulinum neurotoxin isoforms; Clostridia; Duration of neuroparalysis; Endocytosis; Presynaptic binding; Translocation