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J. Biol. Chem., Vol. 282, Issue 19, 14675-14683, May 11, 2007

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Two Synergistic Activation Mechanisms of 21 Integrin-mediated Collagen Binding^*

Wendy L. Connors, Johanna Jokinen, Daniel J. White, J. Santeri Puranen^¶, Pasi Kankaanpää, Paula Upla, Mira Tulla, Mark S. Johnson^¶, and Jyrki Heino¹

From the Department of Biochemistry and Food Chemistry, University of Turku, FI-20014 Turku, Finland, the Department of Biological and Environmental Science, University of Jyväskylä, FI-40014 Jyväskylä, Finland, and ^¶Department of Biochemistry & Pharmacy, Åbo Akademi University, FI-20520 Turku, Finland

Activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces ligand-independent aggregation of a cell surface collagen receptor, 21 integrin. Concomitantly, TPA increases the avidity of 21 for collagen and the number of conformationally activated 21 integrins. The structural change was shown using a monoclonal antibody 12F1 that recognizes the "open" (active) conformation of the inserted domain in the 2 subunit (2I). Amino acid residue Glu-336 in 2 subunit is proposed to mediate the interaction between 2I domain and 1 subunit. Glu-336 seems to regulate a switch between open and "closed" conformations, since the mutation 2E336A inhibited the TPA-related increase in the number of 12F1 positive integrins. E336A also reduced cell adhesion to collagen. However, E336A did not prevent the TPA-related increase in adhesion to collagen or 21 aggregation. Thus, 21 integrin avidity is regulated by two synergistic mechanisms, first an 2E336-dependent switch to the open 2I conformation, and second an 2E336-independent mechanism temporally associated with receptor aggregation.

Received for publication, January 26, 2007 , and in revised form, March 16, 2007.

^* This work was funded by the Academy of Finland, the Technology Development Center of Finland, the Sigrid Jusélius Foundation, the Finnish Cancer Association, the Center of Excellence Program of Åbo Akademi, and the National Graduate School of Informational and Structural Biology. 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 a supplemental movie.

¹ To whom correspondence should be addressed. Tel.: 358-2-333-6879; Fax: 358-2-333-6860; E-mail: jyrki.heino{at}utu.fi.

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