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J. Biol. Chem., Vol. 282, Issue 49, 35868-35877, December 7, 2007

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Fetuin A Stabilizes m-Calpain and Facilitates Plasma Membrane Repair^*

From the Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614

Yeast two-hybrid experiments identified ₂-Heremans-Schmid glycoprotein (human fetuin A) as a binding partner for calpain domain III (DIII). The tandem DIIIs of calpain-10 interacted under the most selective culture conditions, but DIIIs of m-calpain, calpain-3, and calpain-5 also interacted under less stringent selection. DIIIs of µ-calpain, calpain-6, and the tandem DIII-like domains of the Dictyostelium Cpl protein did not interact with ₂-Heremans-Schmid glycoprotein in the yeast two-hybrid system. Bovine fetuin A stabilized proteolytic activity of purified m-calpain incubated in the presence of mM calcium chloride and prevented calcium-dependent m-calpain aggregation. Consistent with the yeast two-hybrid studies, fetuin A neither stabilized µ-calpain nor prevented its aggregation. Confocal immunofluorescence microscopy of scratch-damaged L6 myotubes demonstrated accumulation of m-calpain at the wound site in association with the membrane repair protein, dysferlin. m-Calpain also co-localized with fluorescein-labeled fetuin A at the wound site. The effect of fetuin A on calpain-mediated plasma membrane resealing was investigated using fibroblasts from Capns1^-/- and Capns1^+/+ mouse embryos. Capns1 encodes the small noncatalytic subunit that is required for the proteolytic function of m- and µ-calpains. Thus, Capns1^-/- fibroblasts do not express these calpains in active form. Fetuin A increased resealing of scrape-damaged wild-type fibroblasts but not Capns1^-/- fibroblasts. These studies identify fetuin A as a potential extracellular regulator of m-calpain at nascent sites of plasma membrane wounding.

Received for publication, August 20, 2007 , and in revised form, October 5, 2007.

^* This work was supported in part by a grant from the American Heart Association. 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.

² Present address: Dept. of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.

¹ To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Ave., Toledo, OH 43614-2598. Tel.: 419-383-5307; Fax: 419-383-2871; E-mail: ronald.mellgren{at}utoledo.edu.

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