Integrins are integral membrane proteins found on nearly every cell in multicellular animals. They provide the means by which cells interact with components of the extracellular matrix (ECM). In humans, integrins are heterodimers composed of one of 18 alpha subunits and one of 8 beta subunits, with 24 combinations found in cells. Much of what we know about integrin function comes from studies of the αIIbβ3 protein from platelets. This integrin appears to exist in a default “inactive” form, meaning that it does not bind to its ECM target, fibrinogen. Platelet activation leads to binding of an intracellular protein, talin, to the C-terminus of the integrin, destabilizing two structural “clasps” that bind the alpha and beta subunits to each other and freeing the protein for fibrinogen binding. Despite this detailed knowledge about αIIbβ3, it is unclear to what degree its activation mechanism applies to other integrins. To answer this question, Vanderbilt Basic Sciences researcher Chuck Sanders, his collaborator (Roy Zent) and their laboratories carried out extensive structural and functional studies of α1β1 and α2β1, the major integrins that bind to collagen. For this work, they focused on a particular lysine residue in the β1 subunit, as the homologous residue in the β3 subunit αIIbβ3 plays a key role in the activation of that protein. The researchers discovered that the α1β1 and α2β1 integrins likely exist in a default “active” state, able to bind collagen, and that structural alterations to the key lysine residue that activate αIIbβ3 have the opposite effect on these proteins. Their findings demonstrate that the integrins are structurally and functionally diverse, and that no single mechanism of activation can be generalized to the entire protein class. Clearly further work is needed to fully understand how cells interact with their environment through integrins. The work is published in the journal eLife [Z. Lu, S. Mathew, J. Chen, et al., eLife, 2016:10.7554/eLife.18633].