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J. Biol. Chem., Vol. 268, Issue 29, 21826-21834, 10, 1993
JW Creemers, RJ Siezen, AJ Roebroek, TA Ayoubi, D Huylebroeck and WJ Van de Ven
The proprotein processing activity of mutants of the subtilisin-like enzyme
furin was studied in transfected mammalian cells. Our studies indicate that
the three residues of the catalytic triad of furin, Asp46, His87, and
Ser261, are critical not only for substrate processing but also for
maturation of furin. Furthermore, evidence is provided that maturation of
furin occurs through an intramolecular autocatalytic process. Substitution
of the asparagine residue (Asn188) of the oxyanion hole by an alanine
residue appears to block substrate processing but not furin maturation.
Analysis of carboxyl-terminal deletion mutants revealed that the segment
encompassing residues Glu449 to Glu469 of the "middle" domain, which is
more than 100 residues downstream of the predicted catalytic domain,
contains residues that seem to be critical for processing activity but that
the more carboxyl- terminal cysteine-rich region, the transmembrane region,
and the cytosolic tail are dispensable. Finally, we made mutants in the
substrate binding region of human furin and studied their ability to
process von Willebrand factor (pro-vWF) substrates, including wild-type
pro-vWF as well as pro-vWF mutants in which the P1 (vWFR-1G), P2 (vWFK-
2A), or P4 (vWFR-4A) basic residue with respect to the pro region cleavage
site had been mutated. It is demonstrated that particular negatively
charged residues in or near the substrate binding region of furin are
critical for cleavage activity and specificity of the enzyme for multiple
basic residues in the substrate. Furthermore, substrate binding region
mutants of furin were obtained, which cleaved either the pro-vWFK-2A or
pro-vWFR-4A mutant of pro-vWF more efficiently than wild- type pro-vWF.
Modulation of furin-mediated proprotein processing activity by site- directed mutagenesis
Laboratory for Molecular Oncology, University of Leuven, Belgium.
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