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J. Biol. Chem., Vol. 281, Issue 36, 26455-26464, September 8, 2006

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The Interaction between Calcium- and Integrin-binding Protein 1 and the IIb Integrin Cytoplasmic Domain Involves a Novel C-terminal Displacement Mechanism^*

From the Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada

Calcium- and integrin-binding protein 1 (CIB1) regulates platelet aggregation in hemostasis through a specific interaction with the IIb cytoplasmic domain of platelet integrin IIb₃.In this work we report the structural characteristics of CIB1 in solution and the mechanistic details of its interaction with a synthetic peptide derived from the IIb cytoplasmic domain. NMR spectroscopy experiments using perdeuterated CIB1 together with heteronuclear nuclear Overhauser effect experiments have revealed a well folded -helical structure for both the ligand-free and IIb-bound forms of the protein. Residual dipolar coupling experiments have shown that the N and C domains of CIB1 are positioned side by side, and chemical shift perturbation mapping has identified the IIb-binding site as a hydrophobic channel spanning the entire C domain and part of the N domain. Data obtained with a truncated version of CIB1 suggest that the extreme C-terminal end of the protein weakly interacts with this channel in the absence of a biological target, but it is displaced by the IIb cytoplasmic domain, suggesting a novel mechanism to increase binding specificity.

Received for publication, April 25, 2006 , and in revised form, June 21, 2006.

^* This research was supported by the Canadian Institutes of Health Research. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Funded by studentships from Alberta Heritage Foundation for Medical Research and the Natural Sciences and Engineering Research Council of Canada.

² Holds a postdoctoral fellowship from Alberta Heritage Foundation for Medical Research.

³ To whom correspondence should be addressed: Structural Biology Research Group, Dept. of Biological Sciences, University of Calgary, 2500 University Dr., N. W. Calgary, AB T2N 1N4, Canada. Tel.: 403-220-6006; Fax: 403-289-9311; E-mail: vogel{at}ucalgary.ca.

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