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J. Biol. Chem., Vol. 279, Issue 30, 31533-31543, July 23, 2004

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Comparative Biochemical Analysis Suggests That Vinculin and Metavinculin Cooperate in Muscular Adhesion Sites^*

Sebastian Witt, Anke Zieseniss, Ulrike Fock, Brigitte M. Jockusch, and Susanne Illenberger

From the Cell Biology, Zoological Institute, Technical University of Braunschweig, D-38092 Braunschweig, Germany

Metavinculin, the muscle-specific splice variant of the cell adhesion protein vinculin, is characterized by a 68-amino acid insert within the C-terminal tail domain. The findings that mutations within this region correlate with hereditary idiopathic dilated cardiomyopathy in man suggest a specific contribution of metavinculin to the molecular architecture of muscular actin-membrane attachment sites, the nature of which, however, is still unknown. In mice, metavinculin is expressed in smooth and skeletal muscle, where it co-localizes with vinculin in dense plaques and costameres, respectively, but is of conspicuously low abundance in the heart. Immunoprecipitates suggest that both isoforms are present in the same complex. On the molecular level, both vinculin isoforms are regulated via an intramolecular head-tail interaction, with the metavinculin tail domain having a lower affinity for the head as compared with the vinculin tail. In addition, metavinculin displays impaired binding to acidic phospholipids and reduced homodimerization. Only in the presence of phospholipid-activated vinculin tail, the metavinculin tail domain is readily incorporated into heterodimers. Mutational analysis revealed that the metavinculin insert significantly alters binding of the C-terminal hairpin loop to acidic phospholipids. In summary, our data lead to a model in which unfurling of the metavinculin tail domain is impaired by the negative charges of the 68-amino acid insert, thus requiring vinculin to fully activate the metavinculin molecule. As a consequence, microfilament anchorage may be modulated at muscular adhesion sites through heterodimer formation.

Received for publication, December 29, 2003 , and in revised form, May 4, 2004.

^* This study was supported by the German Research Council (to S. I. and B. M. J.), the Akademie Deutscher Naturforscher Leopoldina (to U. F.), and the Fonds der Chemischen Industrie (to B. M. J.). 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: Cell Biology, Zoological Institute, Technical University of Braunschweig, Biocenter, Spielmannstrasse 7, D-38092 Braunschweig, Germany. Tel.: 49-531-391-3191; Fax: 49-531-391-8203.

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