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Papers In Press, published online ahead of print February 16, 2004
J. Biol. Chem, 10.1074/jbc.M313764200
Submitted on December 16, 2003
Revised on January 20, 2004
Accepted on February 16, 2004
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7
Corresponding Author: seidahn{at}ircm.qc.ca
Processing of membrane-bound transcription factors such as sterol regulatory element binding proteins (SREBPs) and the ER-stress response factor ATF6, and glycoproteins of hemorrhagic fever viruses are initiated by the proprotein convertase SKI-1/S1P. So far, no cellular protein-based inhibitor of the hydrophobic-amino acid specific SKI-1 is known. The prosegment of the basic-amino acid specific convertases (e.g., furin and PC5) or a1-PDX, a variant of a1-antitrypsin (a1-AT) exhibiting an RIPR358 sequence at the reactive site loop, were shown to potently inhibit these secretory proteinases. Accordingly, we tested the SKI-1-inhibitory potential of various point mutants of either the 198 amino acid preprosegment of SKI-11-198 or a1-AT. Transient transfections data showed that, out of numerous mutants studied, the R134E prosegment mutant or the a1-AT reactive site loop variants RRVL358, RRYL358 and RRIL358 are the best specific cellular inhibitors of SKI-1. The observed inhibition of the processing of endogenous SREBP-2, exogenous ATF6 and a PDGF-A (RRLL86) variant were >55% and can reach ~80% in stable transfectants. We also show that SKI-1 forms SDS-stable complexes with these a1-AT variants, but not with wild type a1-AT or a1-PDX. Finally, these inhibitors were also shown to affect the processing and stability of the Crimean-Congo hemorrhagic fever virus glycoprotein.
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