Structural basis of latency in plasminogen activator inhibitor-1

@article{Mottonen1992StructuralBO,
  title={Structural basis of latency in plasminogen activator inhibitor-1},
  author={James Mottonen and Arne Strand and Jindřich Symersk{\'y} and Robert M. Sweet and Dennis Edward Danley and Kieran F. Geoghegan and Robert D. Gerard and Elizabeth J. Goldsmith},
  journal={Nature},
  year={1992},
  volume={355},
  pages={270-273}
}
HUMAN plasminogen activator inhibitor-1 (PAI-1)1,2 is the fast-acting inhibitor of tissue plasminogen activator and urokinase3 and is a member of the serpin family of protease inhibitors4. Serpins normally form complexes with their target proteases that dissociate very slowly as cleaved species and then fold into a highly stable inactive state5 in which the residues that flank the scissile bond (P1 and P1'; ref. 6) are separated by about 70 Å (refs 7–9). PAI-1 also spontaneously folds into a… Expand
Mutational analysis of plasminogen activator inhibitor-1.
TLDR
The data presented identify new determinants of PAI-1 latency transition and provide general insight into the characteristic loop-sheet interactions in serpins. Expand
Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity.
TLDR
It is found that some inhibitors of PAI-1 arrest this serpin in its active form instead of increasing the speed of conversion, which abolishing a necessary step in the conversion of this protein into the latent form. Expand
Crystal Structure of Plasminogen Activator Inhibitor-1 in an Active Conformation with Normal Thermodynamic Stability*
TLDR
The crystal structure of PAI-1 W175F is reported as the first model of the metastable native molecule and 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. Expand
Structural Basis for Recognition of Urokinase-type Plasminogen Activator by Plasminogen Activator Inhibitor-1*
TLDR
This study lays down a foundation for understanding the specificity of PAI-1 for uPA and tPA and provides a structural basis for further functional studies. Expand
Conformational studies on plasminogen activator inhibitor (PAI-1) in active, latent, substrate, and cleaved forms.
Plasminogen activator inhibitor 1 (PAI-1), the primary physiological inhibitor of t-PA, is an unusual member of the serpin family of serine protease inhibitors, in that it spontaneously converts to aExpand
Structure of plasminogen activator inhibitor 1 (PAI-1) and its function in fibrinolysis: an update
TLDR
The structure and function of the PAI-1 protein are described and opportunities for the prevention of reocclusion after thrombolytic treatment of patients, suffering from acute myocardial infarction, by interfering with PAi-1 activity are discussed. Expand
Mechanisms contributing to the conformational and functional flexibility of plasminogen activator inhibitor-1
TLDR
The X-ray structure of a cleaved substrate variant of human PAI-1 has a new β-strand s4A formed by insertion of the amino-terminal portion of the reactive-site loop into β-sheet A subsequent to cleavage. Expand
Distal hinge of plasminogen activator inhibitor-1 involves its latency transition and specificities toward serine proteases
TLDR
The Asp355-Pro357 segment and Glu351 in distal hinge are involved in maintaining the inhibitory conformation of PAI-1, and these mutants have inhibition rate constants which resemble those of the fibrosarcoma inhibitor. Expand
The importance of helix F in plasminogen activator inhibitor-1.
TLDR
The obtained results clearly show the importance of helix F in the inhibitory activity of PAI-1, which apparently leads to an impaired kinetics of insertion of the reactive site loop upon interaction with its target proteinase resulting in the inability to form a stable covalent complex. Expand
Biochemical properties of plasminogen activator inhibitor-1.
TLDR
Studies of PAI-1 have contributed significantly to the elucidation of the protease inhibitory mechanism of serpins, which is based on a metastable native state becoming stabilised by insertion of the RCL into the central beta-sheet A and formation of covalent complexes with target proteases. Expand
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References

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Serpin-resistant mutants of human tissue-type plasminogen activator
TLDR
Although the resulting mutants have enzymatic properties similar to those of wild-type t-PA, they display significant resistance to inhibition by PAI-1. Expand
Restoration of serine protease-inhibitor interaction by protein engineering.
TLDR
The use of protein modeling is used to design a compensatory mutation in PAI-1 (glutamic acid 350 to arginine) and create a molecule that rapidly inhibits this "serpin-resistant" variant of t-PA. Expand
Structure-function studies of the SERPIN plasminogen activator inhibitor type 1. Analysis of chimeric strained loop mutants.
TLDR
Experiments suggest that the strained loop of PAI-1 is not responsible for the transition between the latent and the active conformations or for binding to vitronectin. Expand
Amino acid residues that affect interaction of tissue-type plasminogen activator with plasminogen activator inhibitor 1.
TLDR
A model in which positively charged residues located in a surface loop near the active site of t-PA form ionic bonds with complementary negatively charged residues C-terminal to the reactive center of PAI-1 is proposed. Expand
Plasminogen activator inhibitor 1 (PAI) is bound to vitronectin in plasma
TLDR
The PAI‐binding protein is identical to vitronectin, and NH2‐terminal amino acid sequence analysis and immunoblotting analysis suggested that the two compounds were PAI and vitronECTin. Expand
Bovine endothelial cell plasminogen activator inhibitor. Purification and heat activation.
TLDR
The findings suggest that the buried reactive site of the latent PAI is exposed as a result of a heat-induced, specific conformational change, but tends to be masked again during renaturation under mild conditions, i.e. the PAI protein takes on preferentially a latent form. Expand
Mobile reactive centre of serpins and the control of thrombosis
TLDR
It is shown here that the reactive centre of the serpins can adopt varying conformations and that mobility of the reactive centres is necessary for the function of antithrombin and its binding and activation by heparin and the identification of a new locked conformation explains the latent inactive state of PAI-1. Expand
Plasma serine proteinase inhibitors (serpins) exhibit major conformational changes and a large increase in conformational stability upon cleavage at their reactive sites.
TLDR
From the similarity of the spectral changes and shifts in transition profiles for all four serpins studied, it is concluded that the conformational changes and stabilization triggered by the modification hit is an important common mechanistic feature of this class of inhibitors. Expand
Plakalbumin, α1-antitrypsin, antithrombin and the mechanism of inflammatory thrombosis
An old puzzle in protein biochemistry1 concerns the ready conversion of ovalbumin, by proteolysis, to the much more stable derivative, plakalbumin. Ovalbumin is now known to belong to the serpinExpand
Preliminary x‐ray analysis of crystals of plasminogen activator inhibitor‐1
TLDR
Crystals of bacterially expressed plasminogen activator inhibitor (PAI‐1) suitable for X‐ray diffraction analysis have been obtained from 8% (w/v) PEG 1500, pH 8.25 and contain latent PAI‐ 1 which can be partly reactivated by exposure to denaturants. Expand
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