The integrin reconstruction act

The integrin reconstruction act " I n biology, you really know what you're talking about when you can reconstruct a system synthetically, " says Mark Ginsberg from UC San Diego. That hasn't been possible in the case of integrin activation—the process by which integrin adhesion receptors gain an increased affi nity for their extracellular matrix ligands. The activation mechanism has been highly controversial for more than a decade, partly because the phenomenon hasn't been accurately reca-pitulated with purifi ed proteins in vitro. But a team of scientists has now successfully reconstructed the events leading to integrin activation, which may help settle some of the fi eld's major disputes (1). Integrin activation occurs from the inside out: events in the cytoplasm change the behavior of the integrins' extracellular domains (2). A key event is the binding of a protein called talin to the integrin-␤ subunit's cytoplasmic tail. According to different structural, genetic, and cell biological studies, talin binding may or may not be suffi cient to activate the adhesion receptors—recent reports suggest that a family of proteins called kindlins may be required, too (3). It's also unclear whether activation involves a change in integrin conformation, or whether receptor clustering increases affi nity for the extracellular matrix. On top of that, the role of force in integrin activation has remained elusive, with some suggestions that tension may be required to pull integrins into an active conformation (4). Ye et al. directly tested the contribution of talin to integrin activation by reconstituting the process in vitro with pu-rifi ed integrins inserted into phospholipid liposomes. Addition of the head domain of talin—the key component for integrin acti-vation—was suffi cient to induce the integ-rins to bind their ligand in greater amounts. Whereas kindlins may be involved in integrin activation in cells, it seems talin doesn't need their help in vitro. However, the integrins must be membrane embedded, and mutating a phospholipid-binding site in talin reduced its ability to activate integrins in vitro. The group proposes that the membrane helps orient the talin and its bound integrin-␤ subunit to effect activation (5). But what happens to integrins when they're activated by talin in vitro? Do they undergo a conformational change or do they cluster together? They didn't seem to be clustering on the lipo-some surface, but to answer the question defi nitively, Ye and colleagues immobilized single integrins in lipid nano-discs—10–13-nm phospho-lipid bilayers stabilized by a …