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J. Biol. Chem., Vol. 279, Issue 22, 23637-23645, May 28, 2004

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Coupling of Folding and Binding of Thymosin 4 upon Interaction with Monomeric Actin Monitored by Nuclear Magnetic Resonance^*

Michael Domanski, Maud Hertzog, Jérôme Coutant, Irina Gutsche-Perelroizen¶, François Bontems||, Marie-France Carlier, Eric Guittet, and Carine van Heijenoort**

From the Institut de Chimie des Substances Naturelles, Laboratoire de Chimie et Biologie Structurales and Laboratoire d'Enzymologie et de Biochimie Structurales, Dynamique du Cytosquelette, CNRS, 1 Avenue de la Terrasse, F-91190 Gif sur Yvette, France and ^||Institut de Chimie des Substances Naturelle, CNRS, Antenne de l'Institut de Chimie des Substances Naturelles à l'Ecole Polytechnique, Ecole Polytechnique, F-91128 Palaiseau, France

Thymosin 4 is a major actin-sequestering protein, yet the structural basis for its biological function is still unknown. This study provides insight regarding the way this 43-amino acid peptide, mostly unstructured in solution, binds to monomeric actin and prevents its assembly in filaments. We show here that the whole backbone of thymosin 4 is highly affected upon binding to G-actin. The assignment of all amide protons and nitrogens of thymosin in the bound state, obtained using a combination of NMR experiments and selective labelings, shows that thymosin folds completely upon binding and displays a central extended region flanked by two N- and C-terminal helices. The cleavage of actin by subtilisin in the DNase I binding loop does not modify the structure of thymosin 4 in the complex, showing that the backbone of the peptide is not in close proximity to segment 42-47 of actin. The combination of our NMR results and previously published mutation and cross-link data allows a better characterization of the binding mode of thymosins on G-actin.

Received for publication, October 17, 2003 , and in revised form, March 2, 2004.

The atomic coordinates and structure factors (code 1UY5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

^¶ Present address: Laboratoire de Virologie Moléculaire et Structurale, Centre National de la Recherche Scientifique, 1 Avenue de la Terrasse, F-91190 Gif sur Yvette, France.

^** To whom correspondence should be addressed. Tel.: 33-169823794; Fax: 33-169823784; E-mail: carine{at}icsn.cnrs-gif.fr.

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