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Blood, 1 January 2001, Vol. 97, No. 1, pp. 175-182
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Ligand binding to integrin  v 3
requires tyrosine 178 in the v subunit
Shigenori Honda,
Yoshiaki Tomiyama,
Nisar Pampori,
Hirokazu Kashiwagi,
Teruo Kiyoi,
Satoru Kosugi,
Seiji Tadokoro,
Yoshiyuki Kurata,
Sanford J. Shattil, and
Yuji Matsuzawa
From the Department of Internal Medicine and Molecular
Science, Graduate School of Medicine, Osaka University, and the
Department of Blood Transfusion, Osaka University Hospital, Osaka,
Japan, and the Departments of Vascular Biology and Molecular and
Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
Integrin  v 3 has been implicated
in angiogenesis and other biological processes. However, the
ligand-binding sites in v, a non-I-domain subunit,
remain to be identified. Recently in IIb, the other
partner of the 3 subunit, several discontinuous residues
important for ligand binding were identified in the predicted loops
between repeats 2 and 3 (W3 4-1 loop) and within repeat 3 (W3 2-3 loop). Based on these findings, alanine-scanning mutagenesis in
293 cells was used to investigate the role of these loops (cysteine [C]142-C155 and glycine [G]172-G181) of v in ligand
binding. Wild-type v3 was able to bind
soluble fibrinogen following integrin activation either by 0.5 mM
manganese dichloride (MnCl2) or a mutation of
3 threonine (T)562 to asparagine. However, mutation of
tyrosine (Y)178 to alanine in the predicted G172-G181 loop of
v abolished fibrinogen binding, and alanine (A)
substitutions at adjacent residues phenylalanine (F)177 and tryptophan
(W)179 had a similar effect. Cells expressing Y178Av
also failed to bind to immobilized fibrinogen. Moreover, the Y178A
mutation abolished the binding of WOW-1 Fab, a monovalent
ligand-mimetic anti-v3 antibody, and the
expression of 3 ligand-induced binding sites (LIBS)
induced by arginine-glycine-aspartic acid-tryptophan (RGDW). In sharp
contrast to the data obtained with IIb, none of the mutations in the predicted W3 4-1 loop in v impaired
ligand binding. These results implicate v Y178 in ligand
binding to v3, and they suggest that
there are key structural differences in the adhesive ligand-binding
sites of v3 and
IIb3.
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