title: The C-terminal region of the proprotein convertase 1/3 (PC1/3) exerts a bimodal regulation of the enzyme activity in vitro.
abstract: The proprotein convertase PC1/3 preferentially cleaves its substrates in the dense core secretory granules of endocrine and neuroendocrine cells. Similar to most proteinases synthesized first as zymogens, PC1/3 is synthesized as a larger precursor that undergoes proteolytic processing of its signal peptide and propeptide. The N-terminally located propeptide has been shown to be essential for folding and self-inhibition. Furthermore, PC1/3 also possesses a C-terminal region (CT-peptide) which, for maximal enzymatic activity, must also be cleaved. To date, its role has been documented through transfection studies in terms of sorting and targeting of PC1/3 and chimeric proteins into secretory granules. In this study, we examined the properties of a 135-residue purified bacterially produced CT-peptide on the in vitro enzymatic activity of PC1/3. Depending on the amount of CT-peptide used, it is shown that the CT-peptide increases PC1/3 activity at low concentrations (nm) and decreases it at high concentrations (microm), a feature typical of an activator. Furthermore, we show that, contrary to the propeptide, the CT-peptide is not further cleaved by PC1/3 although it is sensitive to human furin activity. Based on these results, it is proposed that PC1/3, through its various domains, is capable of controlling its enzymatic activity in all regions of the cell that it encounters. This mode of self-control is unique among members of all proteinases families.
authors.affiliation: Neuropeptides Structure and Metabolism Laboratory, Institut de recherches cliniques de Montréal, Québec, Canada.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rabah
authors.forename: Dany
authors.initials: D
authors.lastname: Gauthier
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Dikeakos
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Reudelhuber
authors.forename: Claude
authors.initials: C
authors.lastname: Lazure
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D045683:Furin / Q000737:chemistry; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007313:Insecta; D007700:Kinetics; D051379:Mice; D010455:Peptides / Q000737:chemistry; D045664:Proprotein Convertase 1 / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; D045683:Furin; D045664:Proprotein Convertase 1