TAILIEUCHUNG - Báo cáo khoa học: A steady-state competition model describes the modulating effects of thrombomodulin on thrombin inhibition by plasminogen activator inhibitor-1 in the absence and presence of vitronectin

Thrombomodulin (TM) slows down the interaction rate between thrombin and plasminogen activator inhibitor 1 (PAI-1). We now show that the 12-fold reduced inhibition rate in the presence ofTM does not result from an altered distribution between PAI-1 cleavage and irreversible com-plex formation. Surface plasmon resonance (SPR) revealed an over 200-fold reduced affinity of TM for thrombin-VR1 tPA as compared to thrombin, demonstrating the importance ofthe VR1 loop in the interaction ofthrombin withbothTMandPAI-1 | Eur. J. Biochem. 270 1942-1951 2003 FEBS 2003 doi A steady-state competition model describes the modulating effects of thrombomodulin on thrombin inhibition by plasminogen activator inhibitor-1 in the absence and presence of vitronectin Rob J. Dekker Hans Pannekoek and Anton J. G. Horrevoets Department of Biochemistry Academic Medical Center University of Amsterdam the Netherlands Thrombomodulin TM slows down the interaction rate between thrombin and plasminogen activator inhibitor 1 PAI-1 . We now show that the 12-fold reduced inhibition rate in the presence of TM does not result from an altered distribution between PAI-1 cleavage and irreversible complex formation. Surface plasmon resonance SPR revealed an over 200-fold reduced affinity of TM for thrombin-VR1tPA as compared to thrombin demonstrating the importance of the VR1 loop in the interaciion of thrombin with both TM and PAI-1. Furthermore in contrast to ATIII PAI-1 was not able to bind the thrombin TM complex demonstrating complete competitive binding between PAI-1 and TM. Kinetic modeling on the inhibitory effect of TM confirms a mechanism that involves complete steric blocking ofthe thrombin PAI-1 interaction. Also it accurately decribes the biphasic inhibition profile resulting from the substantial reduction ofthe extremely fast rate ofreversible Michaelis complex formation which is essential for efficient inhibition of thrombin by PAF1. Vítronectín VN is shown to partially relieve TM inhibitory action only by vastly increasing the initial rate of interattían betw-enn free thrombin and PAI-1. In addition SPR established that solution-phase PAI-1 VN complexes and non-native VN extracellular matrix form bind TM directly via the chondroitin sulphate moiety ofTM. Collectively these results show that VR1 is a subsite of te 1 on ttromhi n s s urliiee. which regulates exclusive binding ofeither PAI-1 or TM. This competition will be physiologically significant in .

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