Genetically Determined Proteolytic Cleavage Modulates α7β1 Integrin Function
Genetically Determined Proteolytic Cleavage Modulates α7β1 Integrin Function
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DOI：
10.1074/jbc.m804661200
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发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Kaufman, Stephen J.
中科院分区：
文献类型：
--
作者：
Liu, Jianming;Gurpur, Praveen B.;Kaufman, Stephen J.
The dystrophin-glycoprotein complex and the alpha 7 beta 1 integrin are trans-sarcolemmal linkage systems that connect and transduce contractile forces between muscle fibers and the extracellular matrix. alpha 7 beta 1 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 alpha 7 chains that results from an intra-peptide proteolytic cleavage, by a serine protease, at the (603)RRQ(605) site. Site-directed mutagenesis of RRQ to GRQ prevents this cleavage. This RRQ sequence in the alpha 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 alpha-propeller and thigh domains of the alpha 7 chain. Compared with the non-cleavable alpha 7 chain, the cleaved form enhances cell adhesion and spreading on laminin. Cleavage of the alpha 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 alpha 7 integrin functions in skeletal muscle, and that the generation of such cleavage sites is another evolutionary mechanism for expanding and modifying protein functions.
