PMID: 11917148Mar 28, 2002Paper

Development of selectivity of alpha1-antitrypsin variant by mutagenesis in its reactive site loop against proprotein convertase. A crucial role of the P4 arginine in PACE4 inhibition

Protein Engineering
A TsujiYoshiko Matsuda

Abstract

PACE4, furin and PC6 are Ca2+-dependent serine endoproteases that belong to the subtilisin-like proprotein convertase (SPC) family. Recent reports have supported the involvement of these enzymes in processing of growth/differentiation factors, viral replication, activation of bacterial toxins and tumorigenesis, indicating that these enzymes are a fascinating target for therapeutic agents. In this work, we evaluated the sensitivity and selectivity of three rat alpha1-antitrypsin variants which contained RVPR352, AVRR352 and RVRR352, respectively, within their reactive site loop using both inhibition of enzyme activity toward a fluorogenic substrate in vitro and formation of a SDS-stable protease/inhibitor complex ex vivo. The RVPR variant showed relatively broad selectivity, whereas the AVRR and RVRR variants were more selective than the RVPR variant. The AVRR variant inhibited furin and PC6 but not PACE4. This selectivity was further confirmed by complex formation and inhibition of pro-complement C3 processing. On the other hand, although the RVRR variant inhibited both PACE4 and furin effectively, it needed a 600-fold higher concentration than the RVPR variant to inhibit PC6 in vitro. These inhibitors will be useful tools in h...Continue Reading

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Citations

Mar 30, 2007·Journal of Chromatography. a·Troii HallAlfredo G Tomasselli
Feb 15, 2003·FEBS Letters·Horst PosthausEliane Müller
Jun 11, 2005·Journal of Peptide Science : an Official Publication of the European Peptide Society·Akihiko TsujiYoshiko Matsuda
Nov 5, 2002·The Journal of Biological Chemistry·Nadia NourNabil G Seidah
Mar 10, 2004·The Journal of Biological Chemistry·Rebecca P HugheyThomas R Kleyman
Dec 12, 2002·Chemical Reviews·Nathan C RockwellRobert S Fuller

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