Atypical interactions of integrin αVβ8 with pro-TGF-β1

Integrins alpha(V)beta 6 and alpha(V)beta 8 are specialized for recognizing pro-TGF-beta and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin alpha(V)beta 8 is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine alpha(V)beta 8 for atypical binding to pro-TGF-beta 1. In contrast to alpha(V)beta 6, alpha(V)beta 8 has a constitutive extended-closed conformation, and binding to proTGF- beta 1 does not stabilize the open conformation of its headpiece. Although Mn2+ potently activates other integrins and increases affinity of alpha V beta 6 for pro-TGF-beta 1 25-to 55-fold, it increases alpha V beta 8 affinity only 2-to 3-fold. This minimal effect correlates with the inability of Mn2+ and pro-TGF-beta 1 to stabilize the open conformation of the alpha(V)beta 8 headpiece. Moreover, alpha V beta 8 was inhibited by high concentrations of Mn2+ and was stimulated and inhibited at markedly different Ca2+ concentrations than alpha V beta 6. These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate alpha V beta 8 binding to and activation of pro-TGF-beta.