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Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes
Authors:Wim J M van de Ven  Jan Voorberg  Ruud Fontijn  Hans Pannekoek  Ans M W van den Ouweland  Hans L P van Duijnhoven  Anton J M Roebroek  Roland J Siezen
Institution:(1) Molecular Oncology Section, Center for Human Genetics, University of Leuven, B-3000 Leuven, Belgium;(2) Molecular Oncology Section, Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands;(3) Department of Molecular Biology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands;(4) Department of Biophysical Chemistry, NIZO, Ede, The Netherlands
Abstract:The human fur gene encodes a protein, designated furin, the C-terminal half of which contains a transmembrane and a cysteine-rich receptor-like domain. The N-terminal half of furin exhibits striking primary amino acid sequence similarity to the catalytic domains of members of the subtilisin family of serine proteases. We here report characteristics of the furin protein and propose a three-dimensional model for its presumptive catalytic domain with characteristics, that predict furin to exhibit an endo-proteolytic cleavage selectivity at paired basic residues. This prediction is substantiated by transfection and cotransfection experiments, using COS-1 cells. Full length fur cDNA evokes the specific synthesis of two polypeptides of about 100 kDa and 90 kDa as appeared from Western blot analysis of transfected COS-1 cells using a polyclonal anti-furin antiserum. Functional analysis of furin was performed by cotransfection of fur cDNA with cDNA encoding the lsquowild typersquo precursor of von Willebrand factor (pro-vWF) and revealed an increased proteolytic processing of prov WF. In contrast, cotransfection of fur cDNA with a recombinat derivative (provWFgly763), having the arginine residue adjacent to the proteolytic cleavage site (arg-ser-lys-arg) replaced by glycine, revealed that provWFgly763 is not processed by the fur gene product. We conclude that in higher eukaryotes, furin is the prototype of a subtilisin-like class of proprotein processing enzymes with substrate specificity for paired basic residues.
Keywords:fur gene  furin  proprotein processing  Von Willebrand factor  subtilisin family of serine proteases
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