Atypical interactions of integrin α_Vβ₈ with pro-TGF-β1

Integrins α_Vβ₆ and α_Vβ₈ are specialized for recognizing pro-TGF-β and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin α_Vβ₈ is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine α_Vβ₈ for atypical binding to pro-TGF-β1. In contrast to α_Vβ₆, α_Vβ₈ has a constitutive extended-closed conformation, and binding to pro-TGF-β1 does not stabilize the open conformation of its headpiece. Although Mn²⁺ potently activates other integrins and increases affinity of α_Vβ₆ for pro-TGF-β1 25- to 55-fold, it increases α_Vβ₈ affinity only 2- to 3-fold. This minimal effect correlates with the inability of Mn²⁺ and pro-TGF-β1 to stabilize the open conformation of the α_Vβ₈ headpiece. Moreover, α_Vβ₈ was inhibited by high concentrations of Mn²⁺ and was stimulated and inhibited at markedly different Ca²⁺ concentrations than α_Vβ₆ These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate α_Vβ₈ binding to and activation of pro-TGF-β.