STRUCTURE AND ACTION OF MAMMALIAN RIBONUCLEASE (ANGIOGENIN) INHIBITOR

This chapter discusses the recent studies of the mammalian ribonuclease inhibitor, and in particular, human placental ribonuclease inhibitor (PRI). Far less is known about this protein inhibitor of ribonucleases than about protein inhibitors of proteinases, for which a vast literature exists. Nevertheless, recent studies have revealed distinctive properties of this family of proteins, properties of interest from the point of view of understanding their relation to the inhibition of the activities of the mammalian RNase superfamily of enzymes, including angiogenin in particular. Angiogenin exhibits specific, saturable binding to calf pulmonary endothelial cells. It stimulates phospholipases C and A, in endothelial cells at concentrations as low as 0.1 ng/ml, but is not an endothelial cell mitogen. The 35% identity of the angiogenin primary structure to that of bovine pancreatic ribonuclease A (RNase A) is a most unexpected feature. Three residues catalytically essential in RNase A (Lys-41, His-12, and His-119) are fully conserved in angiogenin. Importantly, the catalytic activity of angiogen is distinct from that of RNase A or other RNases, and this in turn, distinguishes it from all other angiogenic factors. These findings provided a unique opportunity to examine naturally occurring ribonuclease inhibitors for their antiangiogenic properties, and this resulted in the finding that the human protein RNase inhibitor abolishes both the angiogenic and ribonucleolytic and phospholipase C-stimulating activities of angiogenin. © 1993, Academic Press Inc.