Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity

  • Authors:
    • Jerzy Jankun
    • Zofia Specht
    • Maria Szkudlarek
    • Robert Greenfield
    • Bhavna Gaikwad
    • Latchezar Trifonov
    • Jean Vaugeois
    • Ansari M. Aleem
    • Venkatesha Basrur
    • Steven H. Selman
    • Maria I. Zavodszky
    • Ewa Skrzypczak-Jankun
  • View Affiliations

  • Published online on: March 1, 2006     https://doi.org/10.3892/ijmm.17.3.437
  • Pages: 437-447
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Abstract

Plasminogen activator inhibitor-1 (PAI-1), a member of the serpin super-family, forms a covalent complex with its target proteinases, such as tissue and urokinase plasminogen activators. Thus, PAI-1 controls the physiological and pathological proteolysis. An abnormal expression of PAI-1 has been observed in different diseases, which can be treated by returning the proteolysis back to normal physiological levels. It has been reported that some PAI-1 inhibitors neutralize its activity by accelerating the conversion of PAI-1 into a latent form. We have found small organic chemicals that also neutralize PAI-1 activity, but by a different mechanism. Using the NBD fluorescent probe [N,N'-dimethyl-N-(acetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)] incorporated into the reactive center loop (RCL) of PAI-1, we measured the kinetics of conversion from an active to a latent form. Unexpectedly, we found that some inhibitors of PAI-1 arrest this serpin in its active form instead of increasing the speed of conversion. Using docking calculations, we located two possible binding sites for these chemicals. The sites are in proximity of the P1/P1' amino acids of the RCL of PAI-1. Binding in this area can inactivate PAI-1 and additionally create a steric obstacle on the RCL making insertion of this loop between the A3 and A5 strands more difficult; hence abolishing a necessary step in the conversion of this protein into the latent form. Additionally, PAI-1 inhibitors link the RCL of one PAI-1 molecule with the strand 3C and strand 4C or helix A and strand 1B regions of the other PAI-1 molecule aiding polymerization or stabilizing the junction of the two. The polymerization of PAI-1 reduces PAI-1 activity by encapsulating the critical RCL fragment inside the formed PAI-1/PAI-1 polymers.

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March 2006
Volume 17 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Jankun J, Specht Z, Szkudlarek M, Greenfield R, Gaikwad B, Trifonov L, Vaugeois J, Aleem AM, Basrur V, Selman SH, Selman SH, et al: Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity. Int J Mol Med 17: 437-447, 2006.
APA
Jankun, J., Specht, Z., Szkudlarek, M., Greenfield, R., Gaikwad, B., Trifonov, L. ... Skrzypczak-Jankun, E. (2006). Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity. International Journal of Molecular Medicine, 17, 437-447. https://doi.org/10.3892/ijmm.17.3.437
MLA
Jankun, J., Specht, Z., Szkudlarek, M., Greenfield, R., Gaikwad, B., Trifonov, L., Vaugeois, J., Aleem, A. M., Basrur, V., Selman, S. H., Zavodszky, M. I., Skrzypczak-Jankun, E."Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity". International Journal of Molecular Medicine 17.3 (2006): 437-447.
Chicago
Jankun, J., Specht, Z., Szkudlarek, M., Greenfield, R., Gaikwad, B., Trifonov, L., Vaugeois, J., Aleem, A. M., Basrur, V., Selman, S. H., Zavodszky, M. I., Skrzypczak-Jankun, E."Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity". International Journal of Molecular Medicine 17, no. 3 (2006): 437-447. https://doi.org/10.3892/ijmm.17.3.437