Proprotein and prohormone convertases of the subtilisin family Recent developments and future perspectives

Abstract

Limited proteolysis of precursors at specific pairs of basic residues and/or at single basic amino acids is a widespread mechanism by which the cell expresses a repertoire of biologically active proteins and peptides. The cloning and cellular expression of the yeast KEX2 gene product demonstrated that this enzyme belongs to the subtilisin family of serine proteinases, and that it exhibits exquisite selectivity for cleavage post pairs of basic residues in a number of yeast and mammalian precursors. The search for the homologous mammalian convertases led to the identification and molecular cloning of three new members of the family, furin, PCI, and PC2. Whereas furin is almost ubiquitous, PCI and PC2 localize mostly in endocrine and neuroendocrine tissues and cells. Coexpression of each gene product with proproteins demonstrated that each proteinase selectively cleaved these precursors at distinct pairs of LysArg and ArgArg residues. In human and mouse, the genes coding for furin, PCI, and PC2 reside on three different chromosomes. Overexpression of PO and PC2 in Sf9 cells in the baculovirus system demonstrated that these enzymes are not secreted and that they both retained their N-terminal prodomain.