tailieunhanh - Báo cáo Y học: Interaction of plasminogen activator inhibitor type-1 (PAI-1) with vitronectin Characterization of different PAI-1 mutants

The serpin plasminogen activator inhibitor type 1 (PAI-1) plays an important role in physiological processes such as thrombolysis and ®brinolysis, as well as pathophysiological processes such as thrombosis, tumor invasion and metas-tasis. In addition to inhibiting serine proteases, mainly tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, PAI-1 interacts with di erent components of the extracellular matrix, . ®brin, heparin (Hep) and vitronectin (Vn). | Eur. J. Biochem. 269 184-192 2002 FEBS 2002 Interaction of plasminogen activator inhibitor type-1 PAI-1 with vitronectin Characterization of different PAI-1 mutants Nuria Arroyo De Prada1 Florian Schroeck1 Eva-Kathrin Sinner2 Bernd Muehlenweg1 3 Jens Twellmeyer1 Stefan Sperl3 Olaf G. Wilhelm3 Manfred Schmitt1 and Viktor Magdolen1 1Klinische Forschergruppe der Frauenklinik der Technischen Universitat Munchen Klinikum rechts der Isar Germany 2Max-Planck-Institut fur Biochemie Martinsried Germany 3Wilex AG Munchen Germany The serpin plasminogen activator inhibitor type 1 PAI-1 plays an important role in physiological processes such as thrombolysis and fibrinolysis as well as pathophysiological processes such as thrombosis tumor invasion and metastasis. In addition to inhibiting serine proteases mainly tissue-type tPA and urokinase-type uPA plasminogen activators PAI-1 interacts with different components of the extracellular matrix . fibrin. heparin Hep and vitronectin Vn . PAI-1 binding to Vn facilitates migration and invasion of tumor cells. The most important determinants of the Vn-binding site of PAI-1 appear to reside between amino acids 110-147 which includes a helix E hE amino acids 109-118 . Ten different PAI-1 variants mostly harboring modifications in hE as well as wild-type PAI-1 the previously described PAI-1 mutant Q123K and another serpin PAI-2 were recombinantly produced in Escherichia coli containing a His6 tag and purified by affinity chromatography. As shown in microtiter plate-based binding assays surface plasmon resonance and thrombin inhibition experiments all of the newly generated mutants which retained inhibitory activity against uPA still bound to Vn. Mutant A114-118 in which all amino-acids at positions 114-118 of PAI-1 were exchanged for alanine displayed a reduced affinity to Vn as compared to wildtype PAI-1. Mutants lacking inhibitory activity towards uPA did not bind to Vn. Q123K which inhibits uPA but does not bind to Vn served as a .

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