Article

The Phosphotyrosine Binding-like Domain of Talin Activates Integrins

Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2002; 277(24):21749-58. DOI: 10.1074/jbc.M111996200
Source: PubMed

ABSTRACT Cellular regulation of the ligand binding affinity of integrin adhesion receptors (integrin activation) depends on the integrin beta cytoplasmic domains (tails). The head domain of talin binds to several integrin beta 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 beta3 tail. However, talin F3 bound the beta3 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 alpha(IIb)beta3. A molecular model of talin F3 indicated that it resembles a phosphotyrosine-binding (PTB) domain. PTB domains recognize peptide ligands containing beta turns, often formed by NPXY motifs. NPX(Y/F) motifs are highly conserved in integrin beta 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 beta turn at NPX(Y/F) motifs conserved in integrin beta cytoplasmic domains.

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    • "Talin binds to the cytoplasmic tail of integrins through its FERM (Four point one protein/Ezrin/Radixin/Moesin) domain, inducing integrin activation. Talin also binds to F-actin via its C-terminal rod domain (Calderwood et al., 2002; Kim et al., 2012a; Wang, 2012). The mechanosensory properties of talin are confined to the helix bundles present in its rod domain, containing 5 potential vinculin binding sites. "
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    • "The talin head domain (THD) contains four subdomains: F0, F1, F2, and F3. The F3 domain itself can bind to the β3 cytoplasmic domain and exert αIIbβ3 activation [5]. Other subdomains also have important roles in the activation [6-8]. "
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    • "The second and third hot-spots are the membrane distal NxxY and the membrane proximal NPxY motifs (Calderwood et al. 2003). These second and third motifs bind to adaptor proteins that contain PTB domains, such as talin, kindlin 1, kindlin 2 and Shc (Calderwood et al. 2002; Kloeker et al. 2004; Shi et al. 2007). The binding of talin to β-integrin tails via its structurally conserved PTB-like domain results in the separation of the α and β cytoplasmic tails and subsequent integrin activation (Wegener et al. 2007; Wegener and Campbell 2008). "
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