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J. Biol. Chem., Vol. 279, Issue 27, 28531-28538, July 2, 2004

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A Femtomolar Acting Octapeptide Interacts with Tubulin and Protects Astrocytes against Zinc Intoxication^*

Inna Divinski, Leonid Mittelman¶, and Illana Gozes, Holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors||

From the Department of Clinical Biochemistry and ^¶Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

An octapeptide was previously described that protects neurons against a wide variety of insults directly and indirectly as a result of interactions (at femtomolar concentrations) with supporting glial cells. The current study set out to identify the octapeptide binding molecules so as to understand the high affinity mechanisms of cellular protection. Studies utilizing affinity chromatography of brain extracts identified tubulin, the brain major protein, as the octapeptide-binding ligand. Dot blot analysis with pure tubulin and the biotinylated octapeptide verified this finding. When added to cerebral cortical astrocytes, the octapeptide (10^-15–10^-10 M) induced a rapid microtubule reorganization into distinct microtubular structures that were stained by monoclonal tubulin antibodies and visualized by confocal microscopy. Fluorescein-labeled octapeptide induced a similar change and was detected in the intracellular milieu, even when cells were incubated at 4 °C or at low pH. In a cell-free system, the octapeptide stimulated tubulin assembly into microtubules. Furthermore, treatment of astrocytes with zinc chloride resulted in microtubule disassembly and cell death that was protected by the octapeptide. In conclusion, the results suggest that the octapeptide crosses the plasma membrane and interacts directly with tubulin, the microtubule subunit, to induce microtubule reorganization and improved survival. Because microtubules are the key component of the neuronal and glial cytoskeleton that regulates cell division, differentiation, and protection, this finding may explain the breadth and efficiency of the cellular protective capacities of the octapeptide.

Received for publication, March 22, 2004 , and in revised form, April 23, 2004.

^* This work was supported in part by the Institute for the Study of Aging and by the Israel Science Foundation, U.S.-Israel Binational Science Foundation, Institute for the Study of Aging, and Allon Therapeutics, Inc. 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 work is submitted in partial fulfillment of the requirements for a Ph.D. at Tel Aviv University.

^|| To whom correspondence should be addressed. Tel.: 972-3-6407240; Fax: 972-3-6408541; E-mail: igozes{at}post.tau.ac.il.

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