PMID: 2510149Aug 1, 1989Paper

Variants of human tissue-type plasminogen activator substituted at the protease cleavage site and glycosylation sites, and truncated at the N- and C-termini

Protein Engineering
N L HaigwoodE P Pâques

Abstract

Mutations were directed to specific regions of the human tissue-type plasminogen activator (t-PA) gene in an effort to better define structure-function relationships of the enzyme. Three types of modifications were effected by in vitro mutagenesis: elimination of glycosylation sites; substitutions of amino acids at the cleavage site for conversion of single-chain t-PA to two-chain t-PA; and truncations of the N- and C-termini. Thirteen variants were purified from permanent CHO cell lines and analyzed for specific activity, fibrin stimulation, fibrin binding, inhibition by plasminogen activator inhibitor-2 (PAI-2) and half-life. The results of these analyses are: (i) variants with carbohydrate-depleted kringle domains possessed higher specific activities than wild-type t-PA; (ii) a cleavage site variant substituted at Arg275 with Gly had greatly reduced specific activity; (iii) two variants substituted at Lys277 exhibited altered interactions with PAI-2; (iv) the variant with a truncated C-terminus had reduced activity in the absence of fibrin; and (v) no variants had significantly altered half-lives. In order to test the effects of combining mutations, four additional variants were produced. Each combination variant retained at...Continue Reading

Citations

Dec 4, 1992·Annals of the New York Academy of Sciences·M OtterD C Rijken
Jan 11, 2005·Behavioural Processes·C R DahlinC Slobodchikoff
Jul 26, 2017·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Romain GoulayJérôme Parcq
Oct 31, 2009·World Journal of Hepatology·Verena Puxbaum, Lukas Mach
Feb 1, 1992·International Journal of Biological Macromolecules·H WelfleS Y Venyaminov

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