The phosphotyrosine binding-like domain of talin activates Integrins
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.
- SourceAvailable from: Daniel Rösel
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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. "
ABSTRACT: Physicochemical interactions between the cell and its environment are crucial for morphogenesis, tissue homeostasis, remodeling and pathogenesis. Cells form specialized structures like focal adhesions and podosomes that are responsible for bi-directional information exchange between the cell and its surroundings. Besides their role in the transmission of regulatory signals, these structures are also involved in mechanosensing and mechanotransduction. In recent years, many investigations have been carried out to elucidate the mechanisms and consequences of the mechanosensitivity of cells. In this review we discuss the role of the integrin pathway in cellular mechanosensing, focusing on primary mechanosensors, molecules that respond to mechanical stress by changing their conformation. We propose mechanisms by which p130Cas is involved in this process, and emphasize the importance of mechanosensing in cell physiology and the development of diseasesEuropean Journal of Cell Biology 10/2014; 93(10-12). DOI:10.1016/j.ejcb.2014.07.002 · 3.70 Impact Factor
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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). "
ABSTRACT: Integrins are ubiquitously expressed cell surface receptors that play a critical role in regulating the interaction between a cell and its microenvironment to control cell fate. These molecules are regulated either via their expression on the cell surface or through a unique bidirectional signalling mechanism. However, integrins are just the tip of the adhesome iceberg, initiating the assembly of a large range of adaptor and signalling proteins that mediate the structural and signalling functions of integrin. In this review, we summarise the structure of integrins and mechanisms by which integrin activation is controlled. The different adhesion structures formed by integrins are discussed, as well as the mechanical and structural roles integrins play during cell migration. As the function of integrin signalling can be quite varied based on cell type and context, an in depth understanding of these processes will aid our understanding of aberrant adhesion and migration, which is often associated with human pathologies such as cancer.Biophysical Reviews 06/2013; 6(2). DOI:10.1007/s12551-013-0124-0
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- "The integrin α IIb β 3 activation is Ca 2+ -dependent and involves changes in the conformation of both the ligandbinding extracellular region and the cytoplasmic tails (Xiong et al., 2003). Following ligand binding, outside–in signals and altered interactions with cytoskeletal proteins, such tyrosine kinases (Calderwood et al., 2002), control post-adhesion events, such as spreading and contraction in platelet aggregation. "
ABSTRACT: This study was designed to investigate the activity of ethyl acetate extract from Opuntia humifusa Raf. (OH-EAE) in ligand-activated platelet aggregation. Platelet aggregation was induced either by ADP, a potent agonist to platelet G protein-coupled P2Y receptor, by collagen, a potent ligand that activates platelet integrin α2β1 and glycoprotein VI, or thrombin, a platelet protease-activated receptors subtype I and IV. The OH-EAE inhibited platelet aggregation induced by ADP (10 µM) in a dose dependent manner. In addition, OH-EAE significantly and dose-dependently inhibited collagen (2.5 µg/ml)-and thrombin (0.05 U/ml)-induced platelet aggregation. Moreover, the downstream signaling analysis revealed that the extract potently inhibited ADP-induced intracellular calcium mobilization ([Ca 2+ l i). Since degranulation is a marker of platelet activation, the extract effect on the dense granule secretary activity was evaluated. As such, OH-EAE strongly suppressed ADP-induced ATP release. This preliminary result suggests that O. humifusa may be taken as a candidate lead natural compound to be considered in the search for natural products with beneficial effects on aberrant platelet activation mediated cardiovascular disorders.Journal of medicinal plant research 05/2011; 5:1418--1424. · 0.88 Impact Factor