Inhibin, activin and follistatin bind preferentially to the transformed species of alpha(2)-macroglobulin

alpha(2)-Macroglobulin (alpha(2)-M), a major serum glycoprotein, has been implicated as a low-affinity binding protein for inhibin and activin. In serum, alpha(2)-M exists as two major species, a native form that is abundant and stable, and a transformed ('fast') species that is rapidly cleared from the circulation via alpha(2)-M receptors. In this study inhibin, activin and their major binding protein follistatin were investigated for their ability to bind to the native or transformed species of purified human alpha(2)-M. Using native PAGE and size exclusion chromatography, radiolabelled inhibin, activin and follistatin bound to the transformed alpha(2)-M. inhibin and follistatin did not bind significantly to native alpha(2)-M, whereas activin was able to bind to the native species but with a lower capacity compared with that to transformed alpha(2)-M. Under reducing conditions, binding of these hormones to alpha(2)-M was abolished. These findings implicate g-M as a mechanism whereby inhibin, activin and follistatin may be removed from the circulation through alpha(2)-M receptors, but also whereby activin can be maintained in the circulation through its ability to bind to native alpha(2)-M.