DIFFERENTIAL PROTEOLYSIS OF PROHORMONES - IDENTIFICATION OF MAMMALIAN ENDOPROTEASES

In mammals, most active peptide hormones or neuropeptides are released from precursor proteins of higher molecular weight. The specific endoproteases involved in the processing of these precursors have been difficult to isolate and characterize biochemically, primarly due to their low concentrations in the cell. In the yeast Saccharomyces cerevisiae, maturation of the alpha factor pheromone precursor and of the K1 and K2 killer toxin precursors requires the endoprotease Kex2. Expression of this yeast endoprotease in mammalian cells reveals that Kex2 is a potential homologue of the maturation enzymes in higher eukaryotes. Three enzymes have been isolated from mammalian cells based on their sequence similarity with Kex2. These proteins are furin, PC1 and PC2. Studies of localization and substrate specificity of these proteins confirmed their role in processing of prohormones. However, the heterogeneity of the processing sites in prohormones underlines the necessity for the intervention of many other maturation enzymes. Candidates for these other enzymes have been reported.