title: Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes.
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 endoproteolytic 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 'wild type' precursor of von Willebrand factor (pro-vWF) and revealed an increased proteolytic processing of provWF. In contrast, cotransfection of fur cDNA with a recombinant 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.
authors.affiliation: Molecular Oncology Section, University of Leuven, Belgium.
authors.forename: W J
authors.initials: WJ
authors.lastname: van de Ven
authors.forename: J
authors.initials: J
authors.lastname: Voorberg
authors.forename: R
authors.initials: R
authors.lastname: Fontijn
authors.forename: H
authors.initials: H
authors.lastname: Pannekoek
authors.forename: A M
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: H L
authors.initials: HL
authors.lastname: van Duijnhoven
authors.forename: A J
authors.initials: AJ
authors.lastname: Roebroek
authors.forename: R J
authors.initials: RJ
authors.lastname: Siezen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D045683:Furin; D006801:Humans; D007158:Immunologic Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016366:Open Reading Frames; D043484:Proprotein Convertases; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics; D013381:Subtilisins / Q000032:analysis / Q000235:genetics*; D014162:Transfection
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins; C058751:KEX2 protein, S cerevisiae; D045683:Furin