PMID: 2112946Apr 10, 1990Paper

Quenching of the amidolytic activity of one-chain tissue-type plasminogen activator by mutation of lysine-416

Biochemistry
L C PetersenD Foster

Abstract

In contrast to most other serine proteases, tissue-type plasminogen activator (t-PA) possesses enzymatic activity as the one-chain zymogen form. The hypothesis that lysine residues 277 or 416 may be involved in stabilization of an active conformation of one-chain t-PA via salt-bridge formation with aspartic acid residue 477 was tested by site-directed mutagenesis. Four recombinant t-PA mutants were constructed. The amidolytic activities of these analogues were compared to that of authentic t-PA. Substitution of arginine-275 provided an analogue [( R275G]t-PA) resistant to plasmin cleavage. The amidolytic activity of [R275G]t-PA was comparable to that of authentic one-chain t-PA, and so was the activity of [R275L,K277L]t-PA, in which additional substitution of lysine residue 277 was carried out. This suggested that its presence was nonessential for obtaining one-chain t-PA activity. In contrast, substitution of lysine residue 416 to obtain [K416S]t-PA and [K416S,H417T]t-PA resulted in substantial quenching of amidolytic one-chain activity. As expected, the amidolytic activities of the two-chain forms were less affected by the substitution. Involvement of lysine residue 416 in one-chain t-PA activity was also indicated by decreas...Continue Reading

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Citations

Sep 5, 1996·European Journal of Pharmacology·P H AndersenC E Stidsen
Dec 20, 1994·Proceedings of the National Academy of Sciences of the United States of America·I VranesicT Knöpfel
Dec 20, 1994·Proceedings of the National Academy of Sciences of the United States of America·C K TygesenP H Andersen
May 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·A M ShahG L Nelsestuen
Sep 9, 1991·FEBS Letters·T KristensenL Sottrup-Jensen
Sep 23, 2008·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Ana Maria SalazarElda E Sánchez
Jun 1, 1995·Baillière's Clinical Haematology·D C Rijken

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