The β2 subunit forms dimers with at least four types of α subunit and is expressed exclusively on the surface of white blood cells, where it has an essential role in enabling these cells to fight infection. The β2 integrins mainly mediate cell– cell rather than cell–matrix interactions, binding to specific ligands on another cell, such as an endothelial cell. The ligands are members of the Ig superfamily of cell–cell adhesion molecules. We have already described an example earlier in the chapter: an integrin of this class (αLβ2, also known as LFA1) on white blood cells enables them to attach firmly to the Ig family protein ICAM1 on vascular endothelial cells at sites of infection (see Figure 19–28B). People with the genetic disease called leukocyte adhesion deficiency fail to synthesize functional β2 subunits. As a consequence, their white blood cells lack the entire family of β2 receptors, and they suffer repeated bacterial infections.
The β3 integrins are found on blood platelets (as well as various other cells), and they bind several matrix proteins, including the blood clotting factor fibrinogen. Platelets have to interact with fibrinogen to mediate normal blood clotting, and humans with Glanzmann’s disease, who are genetically deficient in β3 integrins, suffer from defective clotting and bleed excessively.
A cell crawling through a tissue—a fibroblast or a macrophage, for example, or an epithelial cell migrating along a basal lamina—has to be able both to make and to break attachments to the matrix, and to do so rapidly if it is to travel quickly. Similarly, a circulating white blood cell has to be able to switch on or off its tendency to bind to endothelial cells in order to crawl out of a blood vessel at a site of inflammation. Furthermore, if force is to be applied where it is needed, the making and breaking of the extracellular attachments in all these cases has to be coupled to the prompt assembly and disassembly of cytoskeletal attachments inside the cell. The integrin molecules that span the membrane and mediate the attachments cannot simply be passive, rigid objects with sticky patches at their two ends. They must be able to switch between an active state, where they readily form attachments, and an inactive state, where they do not.
Structural studies, using a combination of electron microscopy and x-ray crystallography, suggest that integrins exist in multiple structural conformations that reflect different states of activity (Figure 19–57). In the inactive state, the external segments of the integrin dimer are folded together into a compact structure that cannot bind matrix proteins. In this state, the cytoplasmic tails of the dimer are
Figure 19–57 Integrins exist in two major activity states. Inactive (folded) and active (extended) structures of an integrin molecule, based on data from x-ray crystallography and other methods.
Figure 19–58 Activation of integrins by intracellular signaling. Signals received from outside the cell can act through various intracellular mechanisms to stimulate integrin activation. In platelets, as illustrated here, the extracellular signal protein thrombin activates a G-protein-coupled receptor on the cell surface, thereby initiating a signaling pathway that leads to activation of rap1, a member of the monomeric Gtpase family. activated rap1 interacts with the protein rIaM, which then recruits talin to the plasma membrane. together with another protein called kindlin, talin interacts with the integrin β chain to trigger integrin activation. talin then interacts with adaptor proteins such as vinculin, resulting in the formation of an actin linkage (see Figure 19–55).