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J. Biol. Chem., Vol. 282, Issue 19, 14226-14237, May 11, 2007

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A Mutant II-spectrin Designed to Resist Calpain and Caspase Cleavage Questions the Functional Importance of This Process in Vivo^*

Fleur Meary^¶, Sylvain Metral^¶, Chrystophe Ferreira^||, Dominique Eladari^**, Yves Colin^¶, Marie-Christine Lecomte^¶, and Gaël Nicolas^¶1

From the INSERM, U665, Paris F-75015, Institut National de la Transfusion Sanguine, Paris F-75015, ^¶Université Paris 7/Denis Diderot, Paris, F-75005, ^||Institut Fédératif de Recherche Claude Bernard, Faculté de Médecine Xavier Bichat, Paris F-75018, ^**INSERM, U652, Paris F-75006, and Université Paris Descartes, Faculté deMédecine René Descartes, and AP-HP, Département de Physiologie de l'Hôpital Necker-Enfants Malades, Paris F-75006, France

- and -spectrins are components of molecular scaffolds located under the lipid bilayer and named membrane skeletons. Disruption of these scaffolds through mutations in spectrins demonstrated that they are involved in the membrane localization or the maintenance of proteins associated with them. The ubiquitous II-spectrin chain bears in its central region a unique domain that is sensitive to several proteases such as calpains or caspases. The conservation of this region in vertebrates suggests that the proteolysis of II-spectrin by these enzymes could be involved in important functions. To assess the role of II-spectrin cleavage in vivo, we generated a murine model in which the exons encoding the region defining this cleavage sensitivity were disrupted by gene targeting. Surprisingly, homozygous mice expressing this mutant II-spectrin appeared healthy, bred normally, and had no histological anomaly. Remarkably, the mutant II-spectrin assembles correctly into the membrane skeleton, thus challenging the notion that this region is required for the stable biogenesis of the membrane skeleton in nonerythroid cells. Our finding also argues against a critical role of this particular II-spectrin cleavage in either major cellular functions or in normal development.

Received for publication, January 2, 2007 , and in revised form, February 20, 2007.

^* This work was supported by INSERM and by the Institut National de la Transfusion Sanguine. The project was initiated at unit 409 of INSERM. 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.

¹ To whom correspondence should be addressed: INSERM U665, Institut National de la Transfusion Sanguine, 6 Rue Alexandre Cabanel, Paris F-75015, France. Tel.: 33-1-44-49-30-00 (ext. 32-02); Fax: 33-1-43-06-50-19; E-mail: gnicolas{at}idf.inserm.fr.

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