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J. Biol. Chem., Vol. 280, Issue 26, 24775-24783, July 1, 2005
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Stalk Interactions Differentially Regulate Integrin Activation*




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,
IIb
3 and
V
3, 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
V
3 showed robust ligand binding in the presence of Mn2+,
IIb
3 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
IIb
3 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
V
3-fibrinogen interaction was significantly impaired. Notably, a similar disulfide bridge completely abrogated fibrinogen binding to
IIb
3 when
IIb
3 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.
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