Fasciculin, acetylcholinesterase

Bourne, Y., Taylor, P. and Marchot, P. Acetylcholinesterase inhibition by fasciculin. Crystal structure of the complex. Cell 83 503-512,1995. 

Onchidal and fasciculins are natural toxins, which produce their toxicity in mammalian systems by virtue of primarily acetylcholinesterase (AChE) inhibition. AChE hydrolyzes and inactivates acetylcholine, thereby regidating the concentration of the transmitter at the synapse. Termination of activation is normally dependent on dissociation of acetylcholine from the receptor and its subsequent diffusion and hydrolysis, except in diseases where acetylcholine levels are limiting or under AChE inhibition, conditions that increase the duration of receptor activation (Silver, 1963). 

Duran, R., Cervenansky, C., Dajas, F., Tipton, K.F. (1994). Fasciculin inhibition of acetylcholinesterase is prevented by chemical modification of the enzyme at a peripheral site. Biochim. Biophys. Acta 1201 381-8. 

Binding of I-fasciculin to rat brain acetylcholinesterase. The complex still binds diisopropyl fluorophosphate. J. Biol. Chem. 268 12458-67. 

Dajas, F., Bolioli, B., Castello, M.E., Silveira, R. (1987). Rat striatal acetylcholinesterase inhibition by fasciculin (a polypeptide fi-om green mamba snake venom). Neurosci. Lett. 77 87-91. 

Anglister, L., Eichler, J., Szaho, M., Haesaert, B., Salpeter, M.M. (1998). 1251-labeled fasciculin 2 a new tool for quantitation of acetylcholinesterase densities at synaptic sites by EM-autoradiography. J. Neurosci. Methods 81 63-71. 

Kryger, G., Harel, M., Giles, K., Toker, L., Velan, B., Lazar, A., Kronman, C., Barak, D., Ariel, N., Shafferman, A., Silman, L, Sussman, J.L. (2000). Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr. D Biol. Crystallogr. 56 (Pt 11) 1385-94. 

Radio, Z., Kirchhoff, P.D., Quinn, D.M., McCammon, J.A., Taylor, P. (1997). Electrostatic influence on the kinetics of ligand binding to acetylcholinesterase. Distinctions between active center ligands and fasciculin. J. Biol. Chem. IIT. 23265-77. 

Elcock, A. H., Gabdoulline, R. R., Wade, R. C., and McCammon, J. A. (1999). Computer simulation of protein-protein association kinetics Acetylcholinesterase-fasciculin.y. Mol. Biol. 291, 149-162. 

Figure 8 Thermodynamic cycle illustrating the numerical procedure that calculates the rigid-body electrostatic contribution to the dissociation energy of a complex between mouse acetylcholinesterase (large molecule) and fasciculin-2 (small molecule) (complex PDB ID IMAH ). The steps are (1) complex dissociation in a homogeneous dielectric, (2) transfer of isolated components from a homogeneous dielectric into solution with an inhomogeneous dielectric, (3) complex dissociation in an inhomogeneous dielectric, and (4) transfer of complex from a homogeneous dielectric into solution with an inhomogeneous dielectric.

Inhibitors and Substrates with Acetylcholinesterase and its Fasciculin 2 Complex. 

Le Du, M.H., Marchot, R, Bougis, R, et al., 1992. 1.9-A Resolution structure of fasciculin 1, an anti-acetylcholinesterase toxin from green mamba snake venom. J. Biol. Chem. 267, 22122-22130. 

The toxin binds to acetylcholinesterase and renders acetylcholine unhydrolyzed. This causes continuous excitement of the muscle. The inhibition of acetylcholinesterase is seen not only in vitro, but also in vivo. For instance, 80% of the acetylcholinesterase activity in the locus coeruleus was inhibited by the injection of fasciculin 2 in rats (Abo et al., 1989). The inhibition of the enzyme by fasciculin is longlasting, and a 74% inhibition five days after injection was observed (Quillfeldt et al., 1990). 

By inhibiting acetylcholinesterase, fasciculin increased the amplitude and time course of the endplate potential (Lee et al., 1985). Fasciculin also increased the amplitude of the miniature endplate potential (Cervenansky et al., 1991). 

Acetylcholinesterase enveloped in an artificial liposome can also bind to fasciculin (Puu and Koch, 1990). 

Because of the inhibition of acetylcholinesterase, dendrotoxins or other facilitatory toxins enhance the release of acetylcholine. Thus, dendrotoxins and fasciculins have synergistic action that enhances the lethality. 

Abo, V, Viera, L., Silveira, R., and Dajas, F. (1989). Effects of local inhibition of locus caeruleus acetylcholinesterase by fasciculin in rats. Neurosci. Lett. 98 253-257. 

Menez, R., and Ducruix, A. (1990). Rreliminary x-ray analysis of crystals of fasciculin 1, a potent acetylcholinesterase inhibitor from green mamba venom. J. Mol Biol 216 233-234. 

Quillfeldt, J., Raskovsky, S., Dalmaz, C., Dias, M., Huang, C., Netto, C. A., Schneider, F., Izquierdo, L, Medina, J. H., and Silveira, R. (1990). Bilateral injection of fasciculin into the amygdala of rats Effects on two avoidance tasks, acetylcholinesterase activity, and cholinergic muscarinic receptors. Pharmacol. Biochem. Behav. 37 439-444. 

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