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Preferred sequence requirements for cleavage of pro-von Willebrand factor
by propeptide-processing enzymes
A Rehemtulla and RJ Kaufman
Genetics Institute, Cambridge, MA.
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.
Volume 79,
Issue 9,
pp. 2349-2355,
05/01/1992
Copyright © 1992 by The American Society of Hematology
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