talin regulation depends in part on an interaction between its flexible C-terminal rod domain and the N-terminal head domain that contains the integrin-binding site. this interaction is thought to maintain talin in an inactive state when it is free in the cytoplasm. When talin is recruited by rIaM to the plasma membrane, the talin head domain interacts with a phosphoinositide called pI(4,5)p2 (not shown here, but see Figure 15–28), resulting in dissociation of the rod domain. talin unfolds to expose its binding sites for integrin and other proteins.
hooked together, preventing their interaction with cytoskeletal linker proteins. In the active state, the two integrin subunits are unhooked at the membrane to expose the intracellular binding sites for cytoplasmic adaptor proteins, and the external domains unfold and extend, like a pair of legs, to expose a high-affinity matrix-binding site at the tips of the subunits. Thus, the switch from inactive to active states depends on a major conformational change that simultaneously exposes the external and internal ligand-binding sites at the ends of the integrin molecule. External matrix binding and internal cytoskeleton linkages are thereby coupled.
Switching between the inactive and active states is regulated by a variety of mechanisms that vary, depending on the needs of the cell. In some cases, activation occurs by an “outside-in” mechanism: the binding of an external matrix protein, such as the RGD sequence of fibronectin, can drive some integrins to switch from the low-affinity inactive state to the high-affinity active state. As a result, binding sites for talin and other cytoplasmic adaptor proteins are exposed on the tail of the β chain. The binding of these adaptor proteins then leads to attachment of actin filaments to the intracellular end of the integrin molecule (see Figure 19–55). In this way, when the integrin catches hold of its ligand outside the cell, the cell reacts by tying the integrin molecule to the cytoskeleton, so that force can be applied at the point of cell attachment.
The chain of cause and effect can also operate in reverse, from inside to outside. This “inside-out” integrin-activation process generally depends on intracellular regulatory signals that stimulate the ability of talin and other proteins to interact with the β chain of the integrin. Talin competes with the integrin α chain for its binding site on the tail of the β chain. Thus, when talin binds to the β chain, it blocks the intracellular α–βlinkage, allowing the two legs of the integrin molecule to spring apart.
The regulation of “inside-out” integrin activation is particularly well understood in platelets, where an extracellular signal protein called thrombin binds to a specific G-protein-coupled receptor (GPCR) on the cell surface and thereby activates an intracellular signaling pathway that leads to integrin activation (Figure 19–58). It is likely that similar signaling pathways govern integrin activation in numerous other cell types.
Integrins Cluster to Form Strong adhesions
Integrins, like other cell adhesion molecules, differ from cell-surface receptors for hormones and for other extracellular soluble signal molecules in that they usually bind their ligand with lower affinity and are present at a 10–100-fold higher concentration on the cell surface. The Velcro principle, mentioned earlier in the context of cadherin adhesion (see Figure 19–6C), operates here too. Following their activation, integrins cluster together to create a dense plaque in which many integrin molecules are anchored to cytoskeletal filaments. The resulting protein structure can be remarkably large and complex, as seen in the focal adhesion made by a fibroblast on a fibronectin-coated surface culture dish.