Binding of retinoic acid by the inhibitory serpin protein C inhibitor

The serpin superfamily includes inhibitors of serine proteases and noninhib itory members with other functions (e.g. the hormone precursor angiotensino gen and the hormone carriers corticosteroid-binding globulin and thyroxine- binding globulin). It is not known whether inhibitory serpins have addition al, noninhibitory functions. We studied binding of H-3-labeled hydrophobic hormones (estradiol, progesterone, testosterone, cortisol, aldosterone, and all-trans-retinoic acid) to the inhibitory serpins antithrombin III, hepar in cofactor II, plasminogen activator inhibitor-1, and protein C inhibitor (PCI). All-trans- [H-3]retinoic acid bound in a specific dose-dependent and time-dependent way to PCI (apparent K-d=2.43 muM, 0.8 binding sites per mo lecule of PCI). We did not observe binding of other hormones to serpins. In tact and protease-cleaved PCI bound retinoic acid equally well, and retinoi c acid did not influence inhibition of tissue kallikrein by PCI. Gel filtra tion confirmed binding of retinoic acid to PCI in purified systems and sugg ested that PCI may also function as a retinoic acid-binding protein in semi nal plasma. Therefore, our present data, together with the fact that PCI is abundantly expressed in tissues requiring retinoic acid for differentiatio n processes (e.g. the male reproductive tract, epithelia in various organs) , suggest an additional biological role for PCI as a retinoic acid-binding and/or delivering serpin.