The Phosphotyrosine Binding-like Domain of Talin Activates
Integrins*
David A.
Calderwood
,
Boxu
Yan,
Jose M.
de Pereda§,
Begoña García
Alvarez§,
Yosuke
Fujioka,
Robert C.
Liddington§, and
Mark H.
Ginsberg¶
From the Division of Vascular Biology, Department of
Cell Biology, The Scripps Research Institute and the
§ Program on Cell Adhesion, The Burnham Institute,
La Jolla, California 92037
Cellular regulation of the ligand binding
affinity of integrin adhesion receptors (integrin activation) depends
on the integrin 
cytoplasmic domains (tails). The head domain of
talin binds to several integrin tails and activates integrins. This
head domain contains a predicted FERM domain composed of three
subdomains (F1, F2, and F3). An integrin-activating talin fragment was
predicted to contain the F2 and F3 subdomains. Both isolated subdomains bound specifically to the integrin 3 tail.
However, talin F3 bound the 3 tail with a 4-fold higher
affinity than talin F2. Furthermore, expression of talin F3 (but not
F2) in cells led to activation of integrin
IIb3. A molecular model of talin F3 indicated that it resembles a phosphotyrosine-binding (PTB) domain. PTB
domains recognize peptide ligands containing turns, often formed by
NPXY motifs. NPX(Y/F) motifs are highly
conserved in integrin tails, and mutations that disrupt this motif
interfere with both integrin activation and talin binding. Thus,
integrin binding to talin resembles the interactions of PTB domains
with peptide ligands. These resemblances suggest that the activation of
integrins requires the presence of a turn at NPX(Y/F)
motifs conserved in integrin cytoplasmic domains.
*
This work was supported by Grants HL-48728, HL-30915,
and AR-27214 from the National Institutes of Health, and by the Susan G. Komen Breast Cancer Foundation, and the American Heart Association. This is Publication 13988-VB from the Scripps Research Institute.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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