Activity of Secreted Kunitz Domain 1 Variants of Tissue Factor Pathway Inhibitor

Kirk Johnson; Isabel Zaror; Diane Bauer; Yoon Choi; Abla Creasey; Michael Innis

doi:10.1055/s-0037-1615425

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 80(04): 585-587
DOI: 10.1055/s-0037-1615425

Rapid Communication

Schattauer GmbH

Activity of Secreted Kunitz Domain 1 Variants of Tissue Factor Pathway Inhibitor

Kirk Johnson^*

,

Isabel Zaror^*

,

Diane Bauer

¹From the Chiron Technologies, Chiron Corporation, Emeryville, CA, USA

,

Yoon Choi

¹From the Chiron Technologies, Chiron Corporation, Emeryville, CA, USA

,

Abla Creasey

¹From the Chiron Technologies, Chiron Corporation, Emeryville, CA, USA

,

Michael Innis

¹From the Chiron Technologies, Chiron Corporation, Emeryville, CA, USA

› Author Affiliations

Abstract

Summary

Tissue factor pathway inhibitors (TFPI and TFPI-2) are Kunitz domain-type serine protease inhibitors which inhibit factor VIIa/tissue factor (VIIa/TF) complexes in a factor Xa-dependent manner. The VIIa/TF and Xa inhibitory activity has been localized to the first two Kunitz domains, respectively. Unlike TFPI, TFPI-2 has been reported to exhibit significant Xa-independent VIIa/TF inhibitory activity, perhaps due to an arginine at the P₁ residue in the first Kunitz domain of TFPI-2 as opposed to a lysine at the comparable residue in TFPI. Two domain TFPI variants, differing in the first Kunitz domain but containing the second Kunitz domain of TFPI, were constructed and secreted by Saccharomyces cerevisiae in order to test the possibility that a TFPI first Kunitz domain with a P₁ lysine to arginine change or a hybrid containing the TFPI-2 first Kunitz domain may represent more potent VIIa/TF inhibitors. When yeast supernatants were analyzed for specific activity in the Xa-dependent inhibition of VIIa/TF, neither variant was as active as the truncated TFPI.

Full Text

References

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