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The dystrophin-glycoprotein complex and the α7β1 integrin are trans-sarcolemmal linkage systems that connect and transduce contractile forces between muscle fibers and the extracellular matrix. α7β1 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 α7 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 α7 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 α7 chain. Compared with the non-cleavable α7 chain, the cleaved form enhances cell adhesion and spreading on laminin. Cleavage of the α7 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 α7 integrin functions in skeletal muscle, and that the generation of such cleavage sites is another evolutionary mechanism for expanding and modifying protein functions.
