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J. Biol. Chem., Vol. 283, Issue 51, 35668-35678, December 19, 2008

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Genetically Determined Proteolytic Cleavage Modulates 7β1 Integrin Function^*

From the Department of Cell and Developmental Biology, University of Illinois, Urbana, Illinois 61801

The dystrophin-glycoprotein complex and the 7β1 integrin are trans-sarcolemmal linkage systems that connect and transduce contractile forces between muscle fibers and the extracellular matrix. 7β1 is the major laminin binding integrin in skeletal muscle. Different functional variants of this integrin are generated by alternative splicing and post-translational modifications such as glycosylation and ADP-ribosylation. Here we report a species-specific difference in 7 chains that results from an intra-peptide proteolytic cleavage, by a serine protease, at the ⁶⁰³RRQ⁶⁰⁵ site. Site-directed mutagenesis of RRQ to GRQ prevents this cleavage. This RRQ sequence in the 7 integrin chain is highly conserved among vertebrates but it is absent in mice. Protein structure modeling indicates this cleavage site is located in an open region between the β-propeller and thigh domains of the 7 chain. Compared with the non-cleavable 7 chain, the cleaved form enhances cell adhesion and spreading on laminin. Cleavage of the 7 chain is elevated upon myogenic differentiation, and this cleavage may be mediated by urokinase-type plasminogen activator. These results suggest proteolytic cleavage is a novel mechanism that regulates 7 integrin functions in skeletal muscle, and that the generation of such cleavage sites is another evolutionary mechanism for expanding and modifying protein functions.

Received for publication, June 18, 2008 , and in revised form, October 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health NIA Grant AG14632. This work was also supported by the Muscular Dystrophy 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.

¹ To whom correspondence should be addressed: B107 Chemical and Life Sciences Laboratory, 601 South Goodwin Ave., Urbana, IL 61801. Tel.: 217-244-8116; Fax: 217-244-1648; E-mail: stephenk{at}illinois.edu.

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