HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 26, 24775-24783, July 1, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/26/24775    most recent M409548200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kamata, T. Articles by Aiso, S. Search for Related Content PubMed PubMed Citation Articles by Kamata, T. Articles by Aiso, S. Social Bookmarking                      What's this?

Membrane-proximal / Stalk Interactions Differentially Regulate Integrin Activation^*

Tetsuji Kamata, Makoto Handa¶, Yukiko Sato, Yasuo Ikeda||, and Sadakazu Aiso

From the Departments of Anatomy, ^¶Transfusion Medicine and Cell Therapy, and ^||Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan

The affinity of integrin-ligand interaction is regulated extracellularly by divalent cations and intracellularly by inside-out signaling. We report here that the extracellular, membrane-proximal / stalk interactions not only regulate cation-induced integrin activation but also play critical roles in propagating inside-out signaling. Two closely related integrins, IIb3 and V3, share high structural homology and bind to similar ligands in an RGD-dependent manner. Despite these structural and functional similarities, they exhibit distinct responses to Mn²⁺. Although V3 showed robust ligand binding in the presence of Mn²⁺, IIb3 showed a limited increase but failed to achieve full activation. Swapping stalk regions between IIb and V revealed that the stalk, but not the ligand-binding head region, was responsible for the difference. A series of IIb/V domain-swapping chimeras were constructed to identify the responsible domain. Surprisingly, the minimum component required to render IIb3 susceptible to Mn²⁺ activation was the V calf-2 domain, which does not contain any divalent cation-binding sites. The calf-2 domain makes interface with epidermal growth factor 4 and tail domain in three-dimensional structure. The effect of calf-2 domain swapping was partially reproduced by mutating the specific amino acid residues in the calf-2/epidermal growth factor 4- tail domain interface. When this interface was constrained by an artificially introduced disulfide bridge, the Mn²⁺-induced V3-fibrinogen interaction was significantly impaired. Notably, a similar disulfide bridge completely abrogated fibrinogen binding to IIb3 when IIb3 was activated by cytoplasmic tail truncation to mimic inside-out signaling. Thus, disruption/formation of the membrane-proximal / stalk interface may act as an on/off switch that triggers integrin-mediated bidirectional signaling.

Received for publication, August 19, 2004 , and in revised form, April 21, 2005.

^* This work was supported by a health and labor science research grant for research on regulatory science of pharmaceuticals and medical devices from the Ministry of Health, Labor and Welfare; a grant for leading project for biosimulation from the Ministry of Education, Culture, Sports, Science and Technology; a grant from Keio Gijuku Fukuzawa Memorial Fund for the advancement of education and research (to T. K. and M. H.); a grant-in-aid for scientific research (B); a grant-in-aid for COE research; and a national grant-in-aid for the establishment of high-tech research center in a private university (to S. A.). 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.

To whom correspondence should be addressed: Dept. of Anatomy 3S1, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan. Tel.: 81-3-3353-1211 (ext. 63571); Fax: 81-3-5360-1524; E-mail: kamata{at}sc.itc.keio.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Matsumoto, T. Kamata, J. Takagi, K. Iwasaki, and K. Yura Key Interactions in Integrin Ectodomain Responsible for Global Conformational Change Detected by Elastic Network Normal-Mode Analysis Biophys. J., September 15, 2008; 95(6): 2895 - 2908. [Abstract] [Full Text] [PDF]

				D. Varga-Szabo, I. Pleines, and B. Nieswandt Cell Adhesion Mechanisms in Platelets Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 403 - 412. [Abstract] [Full Text] [PDF]

				V. Gupta, A. Gylling, J. L. Alonso, T. Sugimori, P. Ianakiev, J.-P. Xiong, and M. Amin Arnaout The {beta}-tail domain ({beta}TD) regulates physiologic ligand binding to integrin CD11b/CD18 Blood, April 15, 2007; 109(8): 3513 - 3520. [Abstract] [Full Text] [PDF]