Plasminogen activator inhibitor type 1 (PAI-1) is the most efficient physiologic inhibitor of tissue type and urokinase-type plasminogen activators (t-PA and u-PA). Inactivation of exogenous PAs by plasma PAI-1 is a major obstacle in the development of new thrombolytic therapies. The current understanding of PAI-1 function does not distinguish between inhibition of t-PA versus u-PA and does not adequately emphasize the significance of the inhibitor's physiologic cofactor vitronectin (Vn). The non-ionic detergent Triton X-100 perturbs PAI-1-mediated inhibition of t-PA and u-PA through different means, and binding of Vn to PAI-1 significantly prevents these perturbations. Experiments with a mutant PAI-1 suggest that two functional areas in the inhibitor, known as the distal hinge and the sheet A/helix F (sA/hF) region, may contribute differently to the inactivation of t-PA compared to u-PA. Because further understanding of the structural aspects of the PAI-1 mechanism will be of tremendous benefit to the rational design of safer and more efficient thrombolytic agents, this proposal seeks to test the hypothesis that the distal hinge and the sA/hF region of PAI-1 are important to its inhibitory activities. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS048780-03
Application #
7117299
Study Section
NST-2 Subcommittee (NST)
Program Officer
Golanov, Eugene V
Project Start
2004-09-30
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$48,835
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Li, Shih-Hon; Gorlatova, Natalia V; Lawrence, Daniel A et al. (2008) Structural differences between active forms of plasminogen activator inhibitor type 1 revealed by conformationally sensitive ligands. J Biol Chem 283:18147-57