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J. Biol. Chem., Vol. 280, Issue 24, 23018-23023, June 17, 2005

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Identification of Spectrin-like Repeats Required for High Affinity Utrophin-Actin Interaction^*

Inna N. Rybakova and James M. Ervasti

From the Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706

Most studies aimed at characterizing the utrophinactin interaction have focused on the amino-terminal tandem calponin homology domain. However, we recently reported evidence suggesting that spectrin-like repeats of utrophin also participate in binding to actin. Here we expressed several recombinant fragments encoding the utrophin amino-terminal domain alone or in combination with various numbers of spectrin-like repeats. We further quantitatively characterized the actin binding properties of each recombinant utrophin fragment using a high-speed sedimentation assay. To evaluate the capacity of each protein to stabilize actin filaments, we compared the effect of utrophin recombinant fragments and full-length utrophin on 6-propionyl-2-(N,N-dimethylamino)naphthalene actin depolymerization. Our results suggest that, whereas the amino-terminal domain is essential for primary interaction between utrophin and actin, spectrin-like repeats have additive effects on the affinity and stoichiometry of binding. Our data indicate that the amino-terminal domain and first 10 consecutive spectrin-like repeats recapitulate the actin binding activity of full-length utrophin more faithfully than the amino-terminal domain alone. These findings support the model for lateral association of utrophin along the actin filament and provide the molecular basis for designing the most effective utrophin "mini-genes" for treatment of dystrophinopathies.

Received for publication, March 7, 2005

^* This study was supported by an American Heart Association Scientist development grant (to I. N. R.) and National Institutes of Health Grant AR042423 (to J. M. E.). 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.

To whom correspondence should be addressed: Dept. of Physiology, University of Wisconsin, 127 Service Memorial Institute, 1300 University Ave., Madison, WI 53706. Tel.: 608-265-3419; Fax: 608-265-5512; E-mail: ervasti{at}physiology.wisc.edu.

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