α-Actinin Induces a Kink in the Transmembrane Domain of β3-Integrin and Impairs Activation via Talin.

Integrin-mediated signaling is crucial for cell-substrate adhesion and can be triggered from both intra- and extracellular interactions. Although talin binding is sufficient for inside-out activation of integrin, other cytoplasmic proteins such as α-actinin and filamin can directly interfere with talin-mediated integrin activation. Specifically, α-actinin plays distinct roles in regulating αIIbβ3 versus α5β1 integrin. It has been shown that α-actinin competes with talin for binding to the cytoplasmic tail of β3-integrin, whereas it cooperates with talin for activating integrin α5β1. In this study, molecular dynamics simulations were employed to compare and contrast molecular mechanisms of αIIbβ3 and α5β1 activation in the presence and absence of α-actinin. Our results suggest that α-actinin impairs integrin signaling by both undermining talin binding to the β3-integrin cytoplasmic tail and inducing a kink in the transmembrane domain of β3-integrin. Furthermore, we showed that α-actinin promote talin association with β1-integrin by restricting the motion of the cytoplasmic tail and reducing the entropic barrier for talin binding. Taken together, our results showed that the interplay between talin and α-actinin regulates signal transmission via controlling the conformation of the transmembrane domain and altering natural response modes of integrins in a type-specific manner.