The SAAS granin exhibits structural and functional homology to 7B2 and contains a highly potent hexapeptide inhibitor of PC1

Prohormone convertases (PCs) 1 and 2 are thought to mediate the proteolytic cleavage of many peptide precursors. Endogenous inhibitors of both PC1 and PC2 have now been identified; the 7B2 protein is a nanomolar inhibitor of PC2, while the novel protein proSAAS was recently reported to be a micromol ar inhibitor of PC1 [Fricker et al, (2000) J, Neurosci, 20, 639-648]. We he re report evidence that 7B2 and proSAAS exhibit several elements of structu ral and functional homology, Firstly, 26 kDa human, mouse and rat proSAAS, like all vertebrate 7B2s, contain a proline-rich sequence within the first half of the molecule and also contain a C-terminal 40 residue peptide (SAAS CT peptide) separated from the remainder of the protein by a furin consens us sequence. The SAAS CT peptide contains the precise sequence of a hexapep tide previously identified by combinatorial peptide Library screening as a potent inhibitor of PCI, and the vast majority of the inhibitory potency of proSAAS can be attributed to this hexapeptide, Further, like the 7B2 CT pe ptide, SAAS CT-derived peptides represent tight-binding competitive convert ase inhibitors with nanomolar potencies. Lastly, recombinant PCI is able to cleave the proSAAS CT peptide to a product with a mass consistent with cle avage following the inhibitory hexapeptide, Taken together, our results ind icate that proSAAS and 7B2 may comprise two members of a functionally homol ogous family of convertase inhibitor proteins. (C) 2000 Federation of Europ ean Biochemical Societies.