Plasminogen activator inhibitor type-1 interacts exclusively with the proteinase domain of tissue plasminogen activator

Björquist, Petter; Brohlin, Maria; Ehnebom, J.; Ericsson, Maria; Kristiansen, Charlotte; Pohl, Gunnar; Deinum, Johanna

doi:10.1016/0167-4838(94)90184-8

Cited by 27 publications

(17 citation statements)

References 36 publications

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“…To avoid this interaction, all following binding studies were performed using PAI-1 immobilized on the sensor chip and ␣ 1 -acid glycoprotein or vitronectin as the analytes. Consistent with previous studies (44), after covalent coupling of PAI-1 to the dextran surface, ϳ75% of the molecules remained in the right orientation to react with tPA (data not shown). As shown in Fig.…”

Section: Resultssupporting

confidence: 79%

Acute Phase Protein α1-Acid Glycoprotein Interacts with Plasminogen Activator Inhibitor Type 1 and Stabilizes Its Inhibitory Activity

Boncela¹,

Papiewska²,

Fijałkowska³

et al. 2001

Journal of Biological Chemistry

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␣ 1 -Acid glycoprotein, one of the major acute phase proteins, was found to interact with plasminogen activator inhibitor type 1 (PAI-1) and to stabilize its inhibitory activity toward plasminogen activators. This conclusion is based on the following observations: (a) ␣ 1 -acid glycoprotein was identified to bind PAI-1 by a yeast two-hybrid system. Three of 10 positive clones identified by this method to interact with PAI-1 contained almost the entire sequence of ␣ 1 -acid glycoprotein; (b) this protein formed complexes with PAI-1 that could be immunoprecipitated from both the incubation mixtures and blood plasma by specific antibodies to either PAI-1 or ␣ 1 -acid glycoprotein. Such complexes could be also detected by a solid phase binding assay; and (c) the real-time bimolecular interactions monitored by surface plasmon resonance indicated that the complex of ␣ 1 -acid glycoprotein with PAI-1 is less stable than that formed by vitronectin with PAI-1, but in both cases, the apparent K D values were in the range of strong interactions (4.51 ؉ 1.33 and 0.58 ؉ 0.07 nM, respectively). The on rate for binding of PAI-1 to ␣ 1 -glycoprotein or vitronectin differed by 2-fold, indicating much faster complex formation by vitronectin than by ␣ 1 -acid glycoprotein. On the other hand, dissociation of PAI-1 bound to vitronectin was much slower than that from the ␣ 1 -acid glycoprotein, as indicated by 4-fold lower k off values. Furthermore, the PAI-1 activity toward urokinase-type plasminogen activator and tissue-type plasminogen activator was significantly prolonged in the presence of ␣ 1 -acid glycoprotein. These observations suggest that the complex of PAI-1 with ␣ 1 -acid glycoprotein can play a role as an alternative reservoir of the physiologically active form of the inhibitor, particularly during inflammation or other acute phase reactions.

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Section: Resultssupporting

confidence: 79%

Acute Phase Protein α1-Acid Glycoprotein Interacts with Plasminogen Activator Inhibitor Type 1 and Stabilizes Its Inhibitory Activity

Boncela¹,

Papiewska²,

Fijałkowska³

et al. 2001

Journal of Biological Chemistry

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“…47 PAIs form inhibitory complexes with their C-terminus end and the catalytic domain of PAs. 48,49 In addition, inactive t-PA-PAI-1 complexes compete with active t-PA to occupy binding sites on fibrin. 50 By these two mechanisms, the balance between PAs and PAIs might modulate PA activity in tissues.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Aneurysm Development and Rupture by Local Overexpression of Plasminogen Activator Inhibitor-1

Allaire¹,

Hasenstab²,

Kenagy³

et al. 1998

Circulation

130

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Background-Arterial aneurysms exhibit a loss of elastin and an increase in the plasminogen activators urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA). Because u-PA, t-PA, and plasmin have a limited proteolytic activity against elastin, the role of plasminogen activators in the aneurysmal disease is unclear. To investigate this question, we overexpressed plasminogen activator inhibitor-1 (PAI-1), an inhibitor of t-PA and u-PA, in a rat model of aortic aneurysm. Methods and Results-Guinea pig-to-rat aortic xenografts were seeded with syngeneic Fischer 344 rat smooth muscle cells retrovirally transduced with the rat PAI-1 gene (LPSN group) or the vector alone (LXSN group). Some grafts were not seeded with cells (NO group). Western blots showed increased PAI-1 in grafts from the LPSN group compared with LXSN and NO groups. All grafts in the NO group (nϭ8) and 40% in the LXSN group ruptured between days 4 and 14. At 4 weeks in the LXSN group, the remaining unruptured grafts (nϭ6) were aneurysmal (diameter increase Ն100%), whereas in the LPSN group (nϭ6) none of the grafts had ruptured or were aneurysmal. Elastin was preserved in the LPSN group. t-PA, the major PA expressed in the model, was decreased in the LPSN group compared with the other groups, as determined by zymography. Quantitative zymography showed decreased levels of two matrix metalloproteinases (MMPs), a 28-kD caseinase, and activated MMP-9 in the LPSN group. Conclusions-The blockade of plasminogen activators prevents formation of aneurysms and arterial rupture by inhibiting MMP activation. (Circulation. 1998;98:249-255.)

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“…Protein Concentration Determination-The protein concentration after buffer exchange and dilution of stock solutions was determined from the absorbance spectrum between 250 and 350 nm with a NanoDrop ND-1000 (NanoDrop Technologies, Inc., Wilmington, DE) spectrophotometer according to E 280 at pH 7.4 equal to 34.7, 35.8, 116, and 98 mM Ϫ1 cm Ϫ1 for active PAI-1, latent PAI-1, tPA, and VN, respectively (22,45).…”

Section: Methodsmentioning

confidence: 99%

“…The parameters were extracted from the complete titration of active PAI-1 (specific activity ϳ75%) or latent PAI-1, as shown in (45). A similar control experiment was used with a concentration series of active PAI-1 injected over 900 RU immobilized VN (data not shown), and the conditions for linearity were found to be fulfilled also under these conditions.…”

Section: Table 2 Thermodynamic Parameters For Az3976 Interaction Withmentioning

confidence: 99%

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

Fjellström

Deinum

Sjögren

et al. 2013

Journal of Biological Chemistry

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Background: Inhibition of PAI-1 may yield beneficial effects in e.g. cardiovascular diseases and cancer. Results: The small molecule PAI-1 inhibitor, AZ3976, binds latent but not active PAI-1. The structure of the AZ3976⅐latent PAI-1 complex is presented. Conclusion: AZ3976 inhibits PAI-1 by accelerating latency transition, presumably by binding a prelatent form of PAI-1. Significance: This study provides new drug design opportunities for PAI-1 inhibitors.

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Plasminogen activator inhibitor type-1 interacts exclusively with the proteinase domain of tissue plasminogen activator

Cited by 27 publications

References 36 publications

Acute Phase Protein α1-Acid Glycoprotein Interacts with Plasminogen Activator Inhibitor Type 1 and Stabilizes Its Inhibitory Activity

Acute Phase Protein α1-Acid Glycoprotein Interacts with Plasminogen Activator Inhibitor Type 1 and Stabilizes Its Inhibitory Activity

Prevention of Aneurysm Development and Rupture by Local Overexpression of Plasminogen Activator Inhibitor-1

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

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