Neurotoxins domain structures

Dasgupta B (1994) Structures of botulinum neurotoxin, its functional domains, and perspectives on the cristalline type a toxin. In Jankovic J, Hallett M (eds) Therapy with botulinum toxin. Marcel Dekker, New York, pp 15-39... 

Structural homologies between PFTs and other toxins have not been identified. However, the process of membrane permeabilization may be operative in many cases where proteins have to escape from an intracellular compartment. Well known examples are diphtheria toxin, the neurotoxins and anthrax toxin. Specific domains in many intracel-lularly active toxins have in fact been shown to produce pores in artificial lipid bilayers, and membrane permeabilization is thought to form the basis for translocation of the active moieties from the late endo-some to the cytoplasm (reviewed in Montecucco et ai, 1994). The molecular mechanism of this translocation remains obscure. In the... 

Comparative structural analysis of sodium channel genes has permitted the development of testable hypotheses concerning the neurotoxin recognition properties of the sodium channel protein. However, specific elements of the deduced structure have not yet been definitively correlated with the molecular recognition of sodium channel-directed neurotoxins by discrete binding domains. It is, thus, not possible at the present time to know which pharmacological properties are determined by the sodium channel protein per se and which are determined by interactions between it and crucial features of its membrane environment. Clearly, it will be necessary to analyze the effects of specific modifications of sodium channel structure in a defined membrane environment in order to address these and other questions relating to sodium channel function. 

The sodium channel is the target for several classes of natural neurotoxins. These toxins may affect channel function in a variety of ways by binding to specific receptor sites on the a subunit and interacting with specific portions of the channel protein. These toxins have been invaluable probes for channel structure and function and their specific sites have, in some cases, been localized on the channel protein. The inactivation gate is located in the inner loop between S6 of domain ///and SI of domain IV transmembrane segment S4 of each domain contains voltage sensors and several phosphorylation sites by protein kinase and protein kinase C are identified in the inner loops between domains / and //and between domains ///and IV (Figure 17). 

FIGURE 16 Ribbon representation of irregular structures (a) High potential iron-sulfur protein coordinated to a 4Fe-4S cluster, (b) RAG1 DMA binding protein which contains representative examples of Zn-tinger domains, (c) Defensin as example of a membrane toxin stabilized by disulfide bonds, and (d) Chinese bird spider neurotoxin which contains a cystine knot. 

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