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J. Biol. Chem., Vol. 283, Issue 22, 15169-15176, May 30, 2008

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Miniaturization of Scorpion β-Toxins Uncovers a Putative Ancestral Surface of Interaction with Voltage-gated Sodium Channels^*

Lior Cohen, Noa Lipstein, Izhar Karbat, Nitza Ilan, Nicolas Gilles, Roy Kahn, Dalia Gordon¹, and Michael Gurevitz²

From the Department of Plant Sciences, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel and the Commissariat à l'Energie Atomique, Department d'Ingenierie et d'Etudes des Proteines, C.E. Saclay, F-91191 Gif Sur Yvette Cedex, France

The bioactive surface of scorpion β-toxins that interact with receptor site-4 at voltage-gated sodium channels is constituted of residues of the conserved βββ core and the C-tail. In an attempt to evaluate the extent by which residues of the toxin core contribute to bioactivity, the anti-insect and anti-mammalian β-toxins Bj-xtrIT and Css4 were truncated at their N and C termini, resulting in miniature peptides composed essentially of the core secondary structure motives. The truncated β-toxins (Bj-xtrIT and Css4) were non-toxic and did not compete with the parental toxins on binding at receptor site-4. Surprisingly, Bj-xtrIT and Css4 were capable of modulating in an allosteric manner the binding and effects of site-3 scorpion -toxins in a way reminiscent of that of brevetoxins, which bind at receptor site-5. While reducing the binding and effect of the scorpion -toxin Lqh2 at mammalian sodium channels, they enhanced the binding and effect of LqhIT at insect sodium channels. Co-application of Bj-xtrIT or Css4 with brevetoxin abolished the brevetoxin effect, although they did not compete in binding. These results denote a novel surface at Bj-xtrIT and Css4 capable of interaction with sodium channels at a site other than sites 3, 4, or 5, which prior to the truncation was masked by the bioactive surface that interacts with receptor site-4. The disclosure of this hidden surface at both β-toxins may be viewed as an exercise in "reverse evolution," providing a clue as to their evolution from a smaller ancestor of similar scaffold.

Received for publication, February 14, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant 1 U01 NS058039-01 (to M. G.). This work was also supported by the United States-Israel Binational Agricultural Research and Development Grants IS-3928-06 (to M. G. and D. G.) and IS-4066-07 (to D. G. and M. G.) and the Israeli Science Foundation Grants 1008/05 (to D. G.) and 909/04 (M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence may be addressed. Tel.: 972-3-6409844; Fax: 972-3-6406100; E-mail address: dgordon{at}post.tau.ac.il. ² To whom correspondence may be addressed. Tel.: 972-3-6409844; Fax: 972-3-6406100; E-mail address: mamgur{at}post.tau.ac.il.

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