Converting tissue type plasminogen activator into a zymogen. Important role of Lys156.

The Journal of Biological Chemistry
K Tachias, E L Madison

Abstract

In stark contrast to most other members of the chymotrypsin family of serine proteases, tissue type plasminogen activator (t-PA) is not synthesized and secreted as a true zymogen. Instead, single-chain t-PA exhibits very significant catalytic activity. Consequently, the zymogenicity, or ratio of the catalytic efficiencies of the mature, two-chain enzyme and the single-chain precursor, is only 3-9 for t-PA. Both we and others have previously proposed that Lys156 may contribute directly to this exceptional property of t-PA by forming interactions that selectively stabilize the active conformation of the single-chain enzyme. To test this hypothesis we created variants of t-PA in which Lys156 was replaced by a tyrosine residue. As predicted, the K156Y mutation selectively suppressed the activity of the single-chain enzyme and thereby substantially enhanced the enzyme's zymogenicity. In addition, however, this mutation produced a very dramatic increase in the ability of single-chain t-PA to discriminate among distinct fibrin co-factors. Compared with wild type t-PA, one of the variants characterized in this study, t-PA/R15E,K156Y, possessed substantially enhanced response to and selectivity among fibrin co-factors, resistance to inh...Continue Reading

References

Jan 1, 1990·Thrombosis Research. Supplement·H R LijnenD Collen
May 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·E L MadisonR S Bassel-Duby
Jun 29, 1989·Nature·E L MadisonJ F Sambrook
Jan 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·T A Kunkel
Oct 23, 1973·Biochemistry·L A Schick, F J Castellino
Aug 4, 1995·The Journal of Biological Chemistry·K Tachias, E L Madison
Jul 1, 1993·Protein Engineering·N F PaoniW F Bennett
Nov 15, 1996·The Journal of Biological Chemistry·K Tachias, E L Madison

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Citations

Feb 9, 2000·Trends in Biochemical Sciences·M A ParryI Bode
Apr 2, 1999·European Journal of Biochemistry·H Czapinska, J Otlewski
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Nov 25, 2011·BMC Biochemistry·Eugene A CherniavskyVladimir M Shkumatov
Jul 6, 2016·Frontiers in Cellular Neuroscience·Karen-Sue B CarlsonBradford S Schwartz
Nov 16, 2011·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Petra Langerak, Paul Russell
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Aug 26, 1998·The Journal of Biological Chemistry·B SchlottD Collen
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