Inhibitory Specificity and Potency of proSAAS-derived Peptides toward Proprotein Convertase 1

Ajoy Basak, Peter Koch, Marcel Dupelle, Lloyd D. Fricker, Lakshmi A. Devi, Michel Chrétien, Nabil G. Seidah

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52 Scopus citations


Prohormone convertase 1 (PC1), mediating the proteolytic processing of neural and endocrine precursors, is thought to be regulated by the neuroendocrine protein proSAAS. The PC1 inhibitory sequence is mostly confined within a 10-12-amino acid segment near the C terminus of the conserved human proSAAS and contains the critical KR244 dibasic motif. Our results show that the decapeptide proSAAS-(235-244) 235VLGALLRVKR 244 is the most potent reversible competitive PC1-inhibitor (K i ∼9 nM). The C-terminally extended proSAAS-(235-246) exhibits a 5-6-fold higher Ki (∼51 nM). The additional LE sequence at P1′-P2′, resulted in a competitive substrate cleaved by PC1 at KR244 ↓ LE246. Systematic alanine scanning and in some cases lysine scanning tested the contribution of each residue within proSAAS-(235-246) toward the PC1-inhibition's specificity and potency. The amino acids P1 Arg, P2 Lys, and P4 Arg are all critical for inhibition. Moreover, the aliphatic P3 Val and P5, P6, and P1′ Leu significantly affect the degree of enzyme inactivation and PC1 specificity. Interestingly, a much longer N- and C-terminally extended endogenous rat proSAAS-(221-254) called little PenLen, was found to be a 3-fold less potent PC1 inhibitor with reduced selectivity but a much better substrate than proSAAS-(235-246). Molecular modeling studies and circular dichroism analysis indicate an extended and poly-L-proline II type structural conformation for proSAAS-(235-244), the most potent PC1 inhibitor, a feature not present in poor PC1 inhibitors.

Original languageEnglish
Pages (from-to)32720-32728
Number of pages9
JournalJournal of Biological Chemistry
Issue number35
StatePublished - 31 Aug 2001
Externally publishedYes


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