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

Abstract

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 α_IIbβ₃ 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 α_IIbβ₃ 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.