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J. Biol. Chem., Vol. 282, Issue 16, 11914-11920, April 20, 2007

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Tests of the Extension and Deadbolt Models of Integrin Activation^*

Jieqing Zhu, Brian Boylan, Bing-Hao Luo, Peter J. Newman^¶, and Timothy A. Springer¹

From the The CBR Institute for Biomedical Research and Departments of Pathology, Harvard Medical School, Boston, Massachusetts 02115, Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin 53201, and the ^¶Departments of Pharmacology and Cellular Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Despite extensive evidence that integrin conformational changes between bent and extended conformations regulate affinity for ligands, an alternative hypothesis has been proposed in which a "deadbolt" can regulate affinity for ligand in the absence of extension. Here, we tested both the deadbolt and the extension models. According to the deadbolt model, a hairpin loop in the 3 tail domain could act as a deadbolt to restrain the displacement of the 3 I domain 6-7 loop and maintain integrin in the low affinity state. We found that mutating or deleting the 3 tail domain loop has no effect on ligand binding by either IIb 3 or V3 integrins. In contrast, we found that mutations that lock integrins in the bent conformation with disulfide bonds resist inside-out activation induced by cytoplasmic domain mutation. Furthermore, we demonstrated that extension is required for accessibility to fibronectin but not smaller fragments. The data demonstrate that integrin extension is required for ligand binding during integrin inside-out signaling and that the deadbolt does not regulate integrin activation.

Received for publication, January 9, 2007 , and in revised form, February 13, 2007.

^* This work was supported by National Institutes of Health Grants HL48675 (to T. A. S.) and HL44612 (to P. J. N.). 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: The CBR Institute for Biomedical Research and Departments of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. E-mail: springeroffice{at}cbr.med.harvard.edu.

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