tailieunhanh - Báo cáo khoa học: PC1⁄3, PC2 and PC5⁄6A are targeted to dense core secretory granules by a common mechanism

There are seven members of the proprotein convertase (PC) family of secre-ted serine proteases that cleave their substrates at basic amino acids, thereby activating a variety of hormones, growth factors, and viruses. PC1⁄3, PC2 and PC5⁄6A are the only members of the PC family that are targeted to dense core secretory granules, where they carry out the process-ing of proteins that are secreted from the cell in a regulated manner. | ễFEBS Journal PC1 3 PC2 and PC5 6A are targeted to dense core secretory granules by a common mechanism Jimmy D. Dikeakos1 Chantal Mercure1 Marie-Josee Lacombe1 Nabil G. Seidah2 and Timothy L. Reudelhuber1 1 Laboratory of Molecular Biochemistry of Hypertension Institut de Recherches Cliniques de Montreal IRCM QC Canada 2 Laboratory of BiochemicalNeuroendocrinology Institut de Recherches Cliniques de Montreal IRCM QC Canada Keywords alpha helix PC5 6 proprotein convertases regulated secretion secretory granules Correspondence T. L. Reudelhuber IRCM 110 avenue des Pins Ouest Montreal QC Canada H2W 1R7 Fax 1 514 987 5717 Tel 1 514 987 5716 E-mail reudelt@ Received 4 May 2007 revised 7 June 2007 accepted 13 June 2007 doi There are seven members of the proprotein convertase PC family of secreted serine proteases that cleave their substrates at basic amino acids thereby activating a variety of hormones growth factors and viruses. PC1 3 PC2 and PC5 6A are the only members of the PC family that are targeted to dense core secretory granules where they carry out the processing of proteins that are secreted from the cell in a regulated manner. Previous studies have identified a-helices in the C-termini of the PC1 3 and PC2 proteases that are required for this subcellular targeting. In the current study we demonstrate that a predicted a-helix in the C-terminus of PC5 6A is also critical for the ability of this domain to target a heterologous protein to the regulated secretory pathway of mouse endocrine AtT-20 cells. Analysis of the subcellular distribution of fusion proteins containing the C-terminal domains of PC1 3 PC2 and PC5 6A confirmed that all three domains have the capacity to redirect a constitutively secreted protein to the granule-containing cytoplasmic extensions. Analysis of the predicted structures formed by these three granule-sorting helices shows a correlation between their granule-sorting efficiency and the clustering