Abstract
Fibrinolysis is regulated in part by the interaction of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous investigations suggest that three specific arginine residues, Arg-298, Arg-299, and Arg-304 of t-PA, play a critical role in this important regulatory interaction. Our earlier studies have demonstrated that conversion of any of these three residues to a glutamic acid residue reduced the rate of inhibition of t-PA by PAI-1 by factors varying from 58-64. In addition, we have reported that the second order rate constant for inhibition by PAI-1 of the variant t-PA/K296E,R298E,R299E is reduced by a factor of approximately 2800 compared with that of wild type t-PA. In this study, we have significantly extended our earlier observations by identifying t-PA variants that are substantially more resistant to inhibition by PAI-1 than any previously reported variants of t-PA or urokinase-type plasminogen activator. Single-chain t-PA/R275E,R298E, R299E,R304E, for example, is inhibited by PAI-1 approximately 120, 000 times less rapidly than single-chain, wild type t-PA. We also report the first direct comparison of the effects of charge reversal mutations of Arg-298, Arg-299, and/or Arg-...Continue Reading
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