Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.2.717

Neurotoxins Affecting Neuroexocytosis

An overview on the recent developments in the field of liquid crystalline bent-core molecules (so-called banana liquid crystals) is given. After some basic issues, dealing with general aspects of the systematisation of the mesophases, development of polar order and chirality in this class of LC systems and explaining some general structure–property relationships, we focus on fascinating new developments in this field, such as modulated, undulated and columnar phases, so-called B7 phases, phase biaxiality, ferroelectric and antiferroelectric polar order in smectic and columnar phases, amplification and switching of chirality and the spontaneous formation of superstructural and supramolecular chirality.

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Bent-core liquid crystals: polar order, superstructural chirality and spontaneous desymmetrisation in soft matter systems

Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism, a potential biological weapon and an effective therapeutic drug for involuntary muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined at 3.3 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 50 residue loop or belt that wraps around the catalytic domain. This belt partially occludes a large channel leading to a buried, negative active site--a feature that calls for radically different inhibitor design strategies from those currently used. The fold of the translocation domain suggests a mechanism of pore formation different from other toxins. Lastly, the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.

Crystal structure of botulinum neurotoxin type A and implications for toxicity.

Botulinum toxin is a uniquely potent substance synthesized by the organisms Clostridium botulinum, Clostridium baratii, and Clostridium butyricum. This toxin, which acts preferentially on peripheral cholinergic nerve endings to block acetylcholine release, is both an agent that causes disease (i.e., botulism) as well as an agent that can be used to treat disease (e.g., dystonia). The ability of botulinum toxin to produce its effects is largely dependent on its ability to penetrate cellular and intracellular membranes. Thus, toxin that is ingested or inhaled can bind to epithelial cells and be transported to the general circulation. Toxin that reaches peripheral nerve endings binds to the cell surface then penetrates the plasma membrane by receptor-mediated endocytosis and the endosome membrane by pH-induced translocation. Internalized toxin acts in the cytosol as a metalloendoprotease to cleave polypeptides that are essential for exocytosis. This review seeks to identify and characterize all major steps in toxin action, from initial absorption to eventual paralysis of cholinergic transmission.

Identification of the Major Steps in Botulinum Toxin Action

Selected examples of recently synthesised non-conventional liquid crystals are highlighted. These are cyclic and open chain oligoamides, molecules containing tetrahedral or octahedral central cores, dendrimers, polyhydroxy amphiphiles, taper shaped molecules, liquid crystals with perfluorinated or oligosiloxane segments, rod-coil molecules as well as special types of polycatenar and laterally branched calamitic molecules. Their mesomorphic properties are discussed as a consequence of incompatibility, micro-segregation and space filling. The analysis is based on the general concept of amphiphilicity, which describes any chemical or structural contrast within a molecule, such as hydrophilic/lipophilic, polar/non-polar, hydrocarbon/fluorocarbon, oligosiloxane/hydrocarbon or rigid/flexible. These non-conventional liquid crystals will be regarded as block molecules. Depending on the degree of chemical and structural difference and the size of the different building blocks micro-segregation can occur with formation of lamellar, columnar or spheroidal aggregates which organise to smectic, columnar and cubic mesophases. The striking analogies between the polymorphism of thermotropic and lyotropic liquid crystals and block-copolymers are pointed out.

Non-conventional liquid crystals—the importance of micro-segregation for self-organisation

There has been a marked increase during the past 5 years in the number of mesogenic compounds synthesized from the common, naturally occurring carbohydrates, particularly from glucose and glucitol. The structure of the mesophases depends on the shape of the molecules. Cyclic and acyclic carbohydrates with single n-alkyl or acyl chains of more than six carbon atoms are calamitic amphiphiles which form thermotropic smectic Ad phases. The more soluble of these mesogens are used as non-ionic surfactants for solubilizing and crystallizing membrane proteins. They form gels and lyotropic phases with water. The lamellar phase is most common, but some carbohydrate amphiphiles exhibit all of the classical lyotropic phases associated with the ionic surfactants, i.e. lamellar, cubic and hexagonal. Both the smectic Ad and the lamellar Lα phases are believed to be bilayers with interdigitized alkyl chains in the interior of the molecular clusters. The crystal structures of the alkylated cyclic sugars hitherto ...

Carbohydrate liquid crystals

The 2.7 A structure of the tetanus neurotoxin receptor binding fragment Hc reveals a jelly-roll domain and a beta-trefoil domain. Hc retains the unique transport properties of the holotoxin and is capable of eliciting a protective immunological response against the full length holotoxin.

Structure of the receptor binding fragment HC of tetanus neurotoxin.

We propose a different molecular arrangement in the bilayers of the smectic Ad phase of mesogenic Carbohydrate amphiphiles from that previously postulated. The molecular arrangement proposed in this report is consistent with all experimental data currently available. In this new model, the smectic bilayers are identical (except for the absence of water) to the fluid lamellar (Lα) lyotropic phase, i.e., the molecules within the bilayers are arranged tail-to-tail, with the carbohydrate moieties on the outside of the bilaycrs and partially interdigitized alkyl chains in the core of each layer.

A Revised Model for the Molecular Arrangement in the Smectic Ad Phase of Carbohydrate Derived Amphiphiles with One Alkyl Chain

The lyotropic liquid-crystalline behaviour of several dozens of (nonionic) polyhydroxy amphiphiles was studied by observing the penetration of water into the bulk of a sample of amphiphile on a microscope slide and identifying the mesophases observed at the interface with the aqueous solution. The compounds were plotted as a function of the total number of hydroxyl and carbonyl groups vs. the total number of carbon atoms in the (hydrophobic) alkyl chain(s). The symbol used for each compound was chosen to indicate the mesophase observed. In this manner, a clear picture emerged of the relationship between overall molecular structure and type of lyotropic phase(s) formed. Based on this plot it becomes possible to predict the type of lyotropic phase that will be formed at the amphiphile-water interface. Lyotropic mesophases are generally considered to be built up from the aggregates found in dilute aqueous solution. Therefore, a contact preparation also constitutes a simple test for the prediction of the type of aggregate an amphiphile will form in dilute aqueous solution. A useful tool for the design of new surfactants is thus provided.

The relationship between the molecular structure of polyhydroxy amphiphiles and their aggregation behaviour in water. I. The contact preparation method as a tool for empirical studies

The crystal structure of ethylene carbonate, (1,3-dioxolan-2-one), C3H4O3, has been refined from single-crystal neutron diffraction data at 15 K. The crystal data are C2/c, Z = 4, molecular symmetry C2, a = 8.817 (2), b = 6.243 (2), c = 6.644 (2) A, β = 99.31 (1) °. The dioxolan ring has the twist (T) conformation with Cremer-Pople puckering parameters q = 0.2484 (3) A, φ = 270 °. When corrected for thermal motion, the bond lengths are C-C 1.522 A, C-O 1.457 and 1.342 A, CO 1.203 A, C-H 1.091 and 1.097 A. The O-C-C-O torsion angle is 24.8°. Ab initio molecular orbital calculations for the isolated molecule, at rest, using GAUSSIAN-82 with HF/3-21G, 6-31G and 6-31G* bases, also predicted the twist conformation. The 3-21G basis gave the best agreement for the puckering parameter (q = 0.215 A). The difference between calculated and thermally corrected experimental bond lengths ranged between 0.05 A (C-O, 6-31G*) and 0.006 A (C-C, 6-31G*), depending on the basis set used. A calculation of the potential energy surface at HF/3-21G indicates that the transition state is planar and therefore the molecule is not a pseudorotor. A small difference in the methylene C-H bond lengths, which is both observed and predicted by theory, is interpreted as evidence for “lone-pair hyperconjugation” between the nearly axial C-H σ* antibonding orbital and the carbonate π bonding orbital.

Lavinia M. Wingert

Papers

Carbohydrate liquid crystals

Structure of the receptor binding fragment HC of tetanus neurotoxin.

A Revised Model for the Molecular Arrangement in the Smectic Ad Phase of Carbohydrate Derived Amphiphiles with One Alkyl Chain

The relationship between the molecular structure of polyhydroxy amphiphiles and their aggregation behaviour in water. I. The contact preparation method as a tool for empirical studies

Single crystal neutron diffraction analysis (15 K) and ab initio molecular orbital calculations for ethylene carbonate