Changing Ligand Specificities of αvβ1 and αvβ3 Integrins by Swapping a Short Diverse Sequence of the β Subunit*
Abstract
Integrins mediate signal transduction through interaction with multiple cellular or extracellular matrix ligands. Integrin αvβ3 recognizes fibrinogen, von Willebrand factor, and vitronectin, while αvβ1 does not. We studied the mechanisms for defining ligand specificity of these integrins by swapping the highly diverse sequences in the I domain-like structure of the β1 and β3 subunits. When the sequence CTSEQNC (residues 187–193) of β1 is replaced with the corresponding CYDMKTTC sequence of β3, the ligand specificity of αvβ1 is altered. The mutant (αvβ1–3-1), like αvβ3, recognizes fibrinogen, von Willebrand factor, and vitronectin (a gain-of-function effect). The αvβ1–3-1 mutant is recruited to focal contacts on fibrinogen and vitronectin, suggesting that the mutant transduces intracellular signals on adhesion. The reciprocal β3–1-3 mutation blocks binding of αvβ3 to these multiple ligands and to LM609, a function-blocking anti-αvβ3 antibody. These results suggest that the highly divergent sequence is a key determinant of integrin ligand specificity. Also, the data support a recent hypothetical model of the I domain of β, in which the sequence is located in the ligand binding site.
Footnotes
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↵* This work was supported by National Institutes of Health Grants GM47157 and GM49899.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This is publication 10153-VB from The Scripps Research Institute.
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↵¶ Visiting from the Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226, Japan.
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↵§ To whom correspondence should be addressed: Dept. of Vascular Biology, VB-1, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 619-784-7122; Fax: 619-784-7323; E-mail:takada{at}scripps.edu.
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↵1 The abbreviations used are: Fg, fibrinogen; CHO, Chinese hamster ovary; Fn, fibronectin; Vn, vitronectin; vWf, von Willebrand’s factor; mAb, monoclonal antibody; WT, wild type; PBS, phosphate-buffered saline; PIPES, 1,4-piperazinediethanesulfonic acid.
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↵2 T. Kamata and Y. Takada, unpublished results.
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- Received April 22, 1997.
