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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes.

Maturation of pro-von Willebrand factor (vWF) to its active form requires proteolytic processing after a pair of dibasic amino acids (-LysArg-) at residue 763. By coexpression of vWF and various propeptide processing enzymes in COS-1 cells, we here demonstrate that vWF is preferentially processed by the paired dibasic amino acid-cleaving enzyme PACE (furin). Processing of vWF by the yeast homologue of PACE, Kex2, was inefficient and not specific for the authentic site. Two additional recently identified mammalian propeptide-processing enzymes PC2 and PC3 had no detectable vWF-processing activity. The inability of PC2 and PC3 to cleave vWF was apparently not due to the absence of a transmembrane domain, since deletion of the transmembrane domain from PACE resulted in a secreted form which retained its propeptide processing activity within the secretory apparatus. The inability of PC2 and PC3 to process wild-type vWF or any of the vWF mutants described suggests different members of subtilisin-related propeptide-processing enzyme family have evolved to selectively recognize and cleave specific sets of substrates. In addition to paired dibasic residues at the propeptide cleavage site, many proteins, including vWF, also contain an arginine at the P4 position. We have generated mutant vWFs with substitutions at the P2 lysine and/or the P4 arginine to investigate their significance in substrate specificity. A conservative substitution of the P4 arginine by lysine resulted in a decrease in vWF processing by PACE, as did a nonconservative substitution to alanine. Substitution of the P2 lysine to aspartic acid decreased processing and little or no processing was detected when both the P4 and P2 were mutated to lysine and aspartic acid, respectively. These data indicate that both the P4 arginine and the P2 lysine play an important role in substrate recognition by PACE.[1]


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