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First published online January 30, 2004
doi: 10.1242/10.1242/jcs.01014

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Integrin activation

Department of Pharmacology, Yale University School of Medicine, Sterling Hall of Medicine, PO Box 208066, New Haven, CT 06520, USA (e-mail: david.calderwood{at}yale.edu)

View larger version (47K): [in a new window]   Fig. 1. Alignment of integrin cytoplasmic tails. The amino acid sequences of human tails and Drosophila PS1 and Caenorhabditis elegans PAT2 (A), and human ß and Drosophila ßPS and C. elegans ßPAT3 (B) were manually aligned. The divergent human ß4 and ß8 and alternative splice variants of 3, 6, ß1 and ß3 were omitted. The interface between the transmembrane and cytoplasmic regions is generally assumed to lie between the conserved W/Y and K residues, shown in bold. The conserved membrane-proximal subunit GFFKR and ß subunit LLxxxHDREE are shown in red. The conserved ß tail residues involved in talin binding are indicated; the first, ß turn-forming, NPxY motif is shown in blue and the conserved tryptophan is shown in pink.

View larger version (93K): [in a new window]   Fig. 2. Structure of a ß3 tail-talin F3 complex. The structure of the ß3 tail residues 738-748 (shown as sticks) bound to the talin PTB-like domain (PDB: 1MK7). Mutations at talin residues R358, W359 or A360 (shown in green) inhibit ß3 tail binding, whereas mutation of K357 (shown in orange) did not. Integrin residues L746 and W739, which selectively inhibit talin binding and integrin activation when mutated to alanine, are shown in red; Y747, which inhibits talin, filamin and Syk binding when mutated to alanine, is shown in yellow. This figure was first published as Supporting Online Material at Science online (Tadokoro et al., 2003).

View larger version (34K): [in a new window]   Fig. 3. Potential mechanisms regulating talin-mediated integrin activation. Talin binding to integrin ß tails induces conformational changes in the extracellular domain, increasing their affinity for ligands (the nature of the conformational changes remains controversial and the model shown represents only one of several possibilities). Mechanisms that regulate talin binding may therefore control integrin activation. The putative salt bridge stabilizing the interaction between membrane-proximal regions of the and ß tails in the inactive conformation is illustrated as a black bar. The three-lobed FERM domain within the talin head is indicated. (A) Stimulation of talin binding. Two hypothetical models of inactive talin are shown, where regions of the rod mask the ß tail-binding site in the F3 subdomain. Calpain cleavage or PtdIns(4,5)P2 binding unmasks the binding site, potentially activating integrins. (B) Inhibition of talin binding. Src-mediated tyrosine phosphorylation (P) of integrin NPxY motifs, and competition with other ß tail-binding proteins (e.g. PTB domain proteins), or other talin-binding proteins (e.g. PIPKI-90), may prevent integrin-talin interactions, so inhibiting integrin activation. Hence, dynamic interplay between the stimulatory and inhibitory pathways might determine the integrin activation state.