3q02
From Proteopedia
Crystal structure of plasminogen activator inhibitor-1 in a metastable active conformation.
Structural highlights
Disease[PAI1_HUMAN] Defects in SERPINE1 are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:613329]. It is a hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen.[1] Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions. Function[PAI1_HUMAN] Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis.[2] Publication Abstract from PubMedThe serpin plasminogen activator inhibitor-1 (PAI-1) is a crucial regulator in fibrinolysis and tissue remodeling. PAI-1 has been associated with several pathological conditions and is a validated prognostic marker in human cancers. However, structural information about the native inhibitory form of PAI-1 has been elusive due to its inherent conformational instability and rapid conversion to a latent, inactive structure. Here we report the crystal structure of PAI-1 W175F at 2.3 A resolution as the first model of the metastable native molecule. Structural comparison with a quadruple mutant (14-1B) previously used as representative of the active state uncovered key differences. The most striking differences occur near the region that houses three of the four mutations in the 14-1B PAI-1 structure. Prominent changes are localized within a loop connecting beta-strand 3A with the F helix, in which a previously observed 310-helix is absent in the new structure. Notably these structural changes are found near the binding site for the cofactor vitronectin. Since vitronectin is the only known physiological regulator of PAI-1 that slows down the latency conversion, the structure of this region is important. Furthermore, the previously identified chloride binding site close to the F-helix is absent from the present structure and likely to be artifactual, because of its dependence on the 14-1B mutations. Instead we found a different Cl binding site that is likely to be present in wild-type PAI-1 and that more satisfactorily accounts for the Cl stabilizing effect on PAI-1. CRYSTAL STRUCTURE OF PLASMINOGEN ACTIVATOR INHIBITOR-1 IN AN ACTIVE CONFORMATION WITH NORMAL THERMODYNAMIC STABILITY.,Jensen JK, Thompson LC, Bucci JC, Nissen P, Gettins PG, Peterson CB, Andreasen PA, Morth JP J Biol Chem. 2011 Jun 21. PMID:21697084[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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