Biopolym. Cell. 2010; 26(4):255-264.
Огляди
Структурно-функціональні особливості інгібітора активатора плазміногену ПАІ-1
1Жерносєков Д. Д., 1Золотарьова Е. М., 1Кондратюк А. С.
  1. Інститут біохімії ім. О. В. Палладіна НАН України
    вул. Леонтовича, 9, Київ, Україна, 01601

Abstract

ПАІ-1, важливий компонент системи гемостазу, є специфічним інгібітором активаторів плазміногену тканинного (ТПА) та урокіназного типів. ПАІ-1 належить до серпінової родини. Взаємодія з соматоподібним доменом вітронектину стабілізує активну форму інгібітора. Перехід ПАІ-1 до латентного стану пов’язаний з конформаційними змінами у ділянці петлі реактивного центра. Механізм інгібіторної дії ПАІ-1 відповідає класичній схемі серпінового інгібування. ПАІ-1 блокує адгезію опосередковану рецептором УПА та інтегринами, виконуючи при цьому важливу роль в адгезивних процессах та ангіогенезі. Зміни рівня ПАІ-1 розглядають як істотну прогностичну ознаку при захворюваннях серцево-судинної системи, фіброзі нирок, діабеті, канцерогенезі.
Keywords: ПАІ-1, фібриноліз, міграція клітин

References

[1] Ha H., Oh E. Y., Lee H. B. The role of plasminogen activator inhibitor-1 in renal and cardiovascular diseases Nat. Rev. Nephrol 2009 5, N 4:203–211.
[2] Diebold I., Kraicum D., Bonsello S., Gorlach A. The «PAI-1 paradox» in vascular remodeling. Thromb. Haemost 2008 100, N 6:984–991.
[3] Ma L. J., Fogo A. B. Plasminogen activator inhibitor-1 and kidney fibrosis. Front Biosci. 2009 1, N 14:2028–2041.
[4] Matsuzawa Y. The role of fat topology in the risk of disease Int. J. Obes. (Lond) 2008 32, N 7:83–89
[5] Juhan-Vague I., Alessi M. C., Morange P. E. Hypofibrinolysis and increased plasminogen activator inhibitor-1 are linked to atherothrombosis via insulin resistance and obesity Ann. Med 2000 32, N 1:78–84.
[6] Binder B. R., Christ G., Gruber F., Grubic N., Hufnagl P., Krebs M., Mihaly J., Pager G. W. Plasminogen activator inhibitor-1: physiological and pathophysiological roles News Physiol. Sci 2002 17:56–61.
[7] McMahon B., Kwaan H. C. The plasminogen activator system and cancer Pathophys. Haemost. Tromb 2008 36, N 3–4:184–194.
[8] Ulisse S., Baldini E., Sorrenti S., D'Armiento M. The urokinase plasminogen activator system: a target for anticancer therapy Curr. Cancer Drug Targets 2009 9, N 1:32– 71.
[9] Dupont D. M., Madsen J. B., Kristensen T., Bodker J. S., Blou se G. E., Wind T., Andreasen P. A. Biochemical properties of plasminogen activator inhibitor-1 Front. Biosci 2009 14:1337–1361.
[10] Volkov G. L., Platonova T. N., Savchuk A. N., Gornitskaya O. V., Chernyshenko T. M., Krasnobryzhaya E. N. Modern conceptions of hemostasis system Kyiv: Naukova Dumka, 2005 296 p.
[11] Zubairov D. M. Molecular basis of coagulation and thromb formation Kazan: FEN, 2000 364 p.
[12] Declerck P. J., De Mol M., Alessi M. C., Baudner S., Paques E. P., Preissner K. T., Muller-Berghaus G., Collen D. Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin) J. Biol. Chem 1988 263, N 30:15454–15461.
[13] Wiman B., Almquist A., Sigurdadottir O., Lindahl T. Plasminogen activator inhibitor 1 (PAI) is bound to vitronectin in plasma. FEBS Lett 1988 242, N 1:125–128.
[14] Booth N. A., Robbie L. A., Croll A. M., Bennett B. Lysis of platelet-rich thrombi: the role of PAI-1 Ann. Nat. New York Acad. Sci 1992 667:70–80.
[15] Robbie L. A., Bennett B., Croll A. M., Brown P. A., Booth N. A. Proteins of the fibrinolytic system in human thrombi. Thromb. Haemost. 1996; 75, N 1:127–133.
[16] Dellas C., Loskutoff D. J. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease Thromb. Haemost 2005 93, N 4:631–640.
[17] Klinger K. W., Winqvist R., Riccio A., Andreasen P. A., Sartorio R., Nielsen L. S., Stuart N., Stanislovitis P., Watkins P., Douglas R. Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis Proc. Nat. Acad. Sci. USA 1987 84, N 23:8548–8552.
[18] Cicila G. T., O'Connell T. M., Hahn W. C., Rheinwald J. G. Cloned cDNA sequence for the human mesothelial protein «mesosecrin» discloses its identity as a plasminogen activator inhibitor (PAI-1) and a recent evolutionary change in transcript processing. J. Cell Sci 1989 94, N 1:1–10.
[19] Brogren H., Karlsson L., Andersson M., Wang L., Erlinge D., Jern S. Platelets synthesize large amounts of active plasminogen activator inhibitor 1 Blood 2004 104, N 13 P. 3943–3948.
[20] Andreasen P. A., Georg B., Lund L. R., Riccio A., Stacey S. N. Plasminogen activator inhibitors: hormonally regulated serpins. Mol. Cell. Endocrinol 1990 68, N 1:1–19.
[21] De Taeye B., Smith L. H., Vaughan D. E. Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease Curr. Opin. Pharmacol 2005 5:149–215.
[22] Seifert S. C., Gelehrter T. D. Mechanism of dexamethasone inhibition of plasminogen activator in rat hepatoma cells Proc. Nat. Acad. Sci. USA 1978 75, N 12:6130–6133.
[23] Andersen P. A., Riccio A., Welinder K. G., Douglas R., Sartorio R., Nielsen L. S., Oppenheimer C., Blasi F., Dano K. Plasminogen activator inhibitor type-1 reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. FEBS Lett 1986 209, N 2:213–218.
[24] Rheiwald J. G., Jorgensen J. L., Hahn W. C., Terpstra A. J., O'Connell T. M., Plummer K. K. Mesosecrin: a secreted glycoprotein produced in abundance by human mesothelial, endothelial, and kidney epithelial cells in culture J. Cell. Biol 1987 104, N 2:263–275.
[25] Gils A., Pedersen F., Skottrup P., Christensen A., Naessens D., Deinum J., Enghild J. J., Declerck P. J., Andreasen P. A. Biochemical importance of glycosylation of plasminogen activator inhibitor-1. Thromb. Haemost 2003 90, N 2 P. 206–217.
[26] Brogren H., Sihlbom C., Wallmark K., Lonn M., Deinum J., Karlsson L., Jern S. Heterogeneous glycosylation patterns of human PAI-1 may reveal its cellular origin Thromb. Res 2008 122, N 2:271–278.
[27] Serrano R., Barrenetxe J., Orbe J., Rodriguez J. A., Gallardo N., Martinez C., Andres A., Paramo J. A. Tissue-specific PAI-1 gene expression and glycosylation pattern in insulinresistant old rats Am. J. Physiol. Regul. Integr. Comp. Physiol 2009 297, N 5:R1563–R1569.
[28] Mimuro J., Loskutoff D. J. Purification of a protein from bovine plasma that binds to type 1 plasminogen activator inhibitor and prevents its interaction with extracellular matrix. Evidence that the protein is vitronectin. J. Biol. Chem. 1989; 264, N 2:936–939.
[29] Preissner K. T., Seiffert D. Role of vitronectin and its receptors in haemostasis and vascular remodeling Thromb. Res 1998 89, N 1:1–21.
[30] Preissner K. T., Holzhuter S., Justus C., Muller-Berghaus G. Identification of and partial characterization of platelet vitronectin: evidence for complex formation with platelet-derived plasminogen activator inhibitor-1. Blood. 1989; 74, N 6 P. 1989–1996.
[31] Lang I. M., Schleef R. R. Calcium-dependent stabilization of type I plasminogen activator inhibitor within platelet alphagranules J. Biol. Chem 1996 271, N 5:2754–2761.
[32] Seiffert D., Schleef R. R. Two functionally distinct pools of vitronectin (Vn) in the blood circulation: identification of a heparin-binding competent population of Vn within platelet alpha-granules. Blood. 1996; 88, N 2:552–560.
[33] Parker C. J., Stone O. L., White V. F., Bernshaw N. J. Vitronectin (S protein) is associated with platelets Br. J. Haematol 1989 71, N 2:245–252.
[34] Podor T. J, Singh D., Chindemi P., Foulon D. M., McKelvie R., Weitz J. I., Austin R., Boudreau G., Davies R. Vimentin exposed on activated platelets and platelet microparticles localizes vitronectin and plasminogen activator inhibitor complexes on their surface J. Biol. Chem 2002 277, N 9 P. 7529–7539.
[35] Lawrence D. A., Berkenpas M. B., Palaniappan S., Ginsburg D. Localization of vitronectin binding domain in plasminogen activator inhibitor-1. J. Biol. Chem. 1994; 269, N 21 P. 15223–15228.
[36] De Prada N. A., Schroeck F., Sinner E. K., Muehlenweg B., Twellmeyer J., Sperl S., Wilhelm O. G., Schmitt M., Magdolen V. Interaction of plasminogen activator inhibitor type-1 (PAI1) with vitronectin. Eur. J. Biochem 2002 269, N 1 P. 184–192.
[37] Mayasundari A., Whittemore N. A., Serpersu E. H., Peterson C. B. The solution structure of the N-terminal domain of human vitronectin J. Biol. Chem 2004 279, N 28 P. 29359–29366.
[38] Sigurdardottir O., Wiman B. Complex formation between plasminogen activator inhibitor 1 and vitronectin in purified systems and in plasma. Biochim. Biophys. Acta 1990 1035, N 1:56–61.
[39] Seiffert D., Loskutoff D. J. Evidence that type 1 plasminogen activator inhibitor binds to the somatomedin B domain of vitronectin. J. Biol. Chem. 1991; 266, N 5:2824–2830.
[40] Okumura Y., Kamikubo Y., Curriden S. A., Wang J., Kiwada T., Futaki S., Kitagawa K., Loskutoff D. J. Kinetic analysis of the interaction between vitronectin and the urokinase receptor J. Biol. Chem 2002 277, N 11:9395–9404.
[41] Stefansson S., Lawrence D. A. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin Nature 1996 383, N 6599:441–443.
[42] Sancho E., Declerck P. J., Price N. C., Kelly S. M., Booth N. A. Conformational studies on plasminogen activator inhibitor (PAI-1) in active, latent, substrate, and cleaved forms Biochemistry 1995 34, N 3:1064–1069.
[43] Hekman C. M., Loskutoff D. J. Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants J. Biol. Chem. 1985; 260, N 21:11581–11587.
[44] Levin E. G., Santell L. Conversion of the active to latent plasminogen activator inhibitor from human endothelial cells. Blood. 1987; 70, N 4:1090–1098.
[45] Loskutoff D. J., Sawdey M., Mimuro J. Type 1 plasminogen activator inhibitor. Prog. Hemost. Thromb. 1989; 9 P. 87–115.
[46] Lawrence A., Palaniappan S., Stefansson S., Olson S. T., Francis-Chmura A. M., Shore J. D., Ginsburg D. Characterization of the binding of different conformational forms of plasminogen activator inhibitor-1 to vitronectin. Implications for the regulation of pericellular proteolysis J. Biol. Chem. 1997 272, N 12:7676–7680.
[47] Lambers J. W., Cammenga M., Konig B. W., Mertens K., Pannekoek H., van Mourik J. A. Activation of human endothelial cell-type plasminogen activator inhibitor (PAI-1) by negatively charged phospholipids J. Biol. Chem. 1987 262, N 36:17492–17496.
[48] Stoop A. A., Eldering E., Dafforn T. R., Read R. J., Pannekoek H. Different structural requirements for plasminogen activator inhibitor 1 during latency transition and proteinase inhibition as evidenced by phage-displayed hypermutated PAI-1 libraries J. Mol. Biol 2001 305, N 4:773– 783.
[49] Bode W., Huber R. Proteinase-protein inhibitor interactions. Fibrinolysis 1994 8, N 1:161–171.
[50] Kruger P., Verheyden S., Declerck P. J., Engelborghs Y. Extending the capabilities of targeted molecular dynamics: simulation of a large conformational transition in plasminogen activator inhibitor 1 Protein Sci 2001 10, N 4:798– 808.
[51] Gils A., Lu J., Aertgeerts K., Knockaert I., Declerck P. J. Identification of positively charged residues contributing to the stability of plasminogen activator inhibitor 1. FEBS Lett 1997 415, N 2:192–195.
[52] Na Y. R., Im H. Specific interactions of serpins in their native forms attenuate their conformational transitions Protein Sci 2007 16, N 8:1659–1666.
[53] Stout T. J., Graham H., Buckley D. I., Matthews D. J. Structures of active and latent PAI-1: a possible stabilizing role for chloride ions Biochemistry 2000 39, N 29:8460–8469.
[54] Fa M., Karolin J., Aleshkov S., Strandberg L., Johansson L. B., Ny T. Time-resolved polarized fluorescence spectroscopy studies of plasminogen activator inhibitor type 1: conformational changes of the reactive center upon interactions with target proteases, vitronectin and heparin Biochemistry 1995 34, N 42:13833–13840.
[55] Gibson A., Baburaj K., Day D. E.,Verhamme I., Shore J. D., Peterson C. B. The use of fluorescent probes to characterize conformational changes in the interaction between vitronectin and plasminogen activator inhibitor-1 J. Biol. Chem 1997 272, N 8:5112–5121.
[56] Zhou A., Huntington J. A., Pannu N. S., Carrell R. W., Read R. J. How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration Nat. Struct. Biol 2003 10, N 7 P. 541–544.
[57] Hansen M., Busse M. N., Andreasen P. A. Importance of the amino-acid composition of the shutter region of plasminogen activator inhibitor-1 for its transition to latent and substrate forms Eur. J. Biochem 2001 268, N 23:6274–6283.
[58] Sui G. S., Wiman B. Stability of plasminogen activator inhibitor-1: role of tyrosine 221 FEBS Lett 1998 423, N 3 P. 319–323.
[59] Li S-H., Gorlatova N. V., Lawrence D. A., Schwartz B. S. Structural differences between active forms of plasminogen activator inhibitor type 1 revealed by conformationally sensitive ligands J. Biol. Chem 2008 283, N 26:18147–18157.
[60] Silverman G. A., Bird P. I., Carrell R. W., Church F. C., Couglin P. B., Gettins P. G. W., Irving J. A., Ljmas D. A., Luke C. J., Moyer R. W., Pemberton P. A., Remold-O'donnell E., Salversen G. S., Travis J., Whisstock J. C. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins J. Biol. Chem 2001 276, N 36– P. 33293–33296.
[61] Ye S., E. J. Goldsmith E. J. Serpins and other covalent protease inhibitors Curr. Opin. Struct. Biol 2001 11, N 6 P. 740–745.
[62] Wind T., Hansen M., Jensen J. K., Andreasen P. A. The molecular basis for anti-proteolytic and non-proteolytic functions of plasminogen activator inhibitor type-1: roles of the reactive centre loop, the shutter region, the flexible joint region and the small serpin fragment J. Biol. Chem 2002 383, N 1:21–36.
[63] Lawrence D. A., Strandberg L., Ericson J., Ny T. Structurefunction studies of the SERPIN plasminogen activator inhibitor type 1. Analysis of chimeric strained loop mutants. J. Biol. Chem. 1990; 265, N 33:20293–20301.
[64] Sherman P. M., Lawrence D. A., Yang A. Y., Vandenberg E. T., Paielli D., Olson S. T., Shore J. D., Ginsburg D. Saturation mutagenesis of the plasminogen activator inhibitor-1 reactive center. J. Biol. Chem. 1992; 267, N 11:7588– 7595.
[65] Sherman P. M., Lawrence D. A., Paielli V. D., Shore J. D., Ginsburg D. Identification of tissue-type plasminogen activator-specific plasminogen activator inhibitor-1 mutants. Evidence that second sites of interaction contribute to target specificity J. Biol. Chem. 1995 270, N 16:9301– 9306.
[66] York J. D., Li P., Gardell S. J. Combinatorial mutagenesis of the reactive site region in plasminogen activator inhibitor I. J. Biol. Chem 1991 266, N 16:8495–8500.
[67] Egelund R., Rodenburg K. W., Andreasen P. A., Rasmussen M. S., Guldberg R. E., Petersen T. E. An ester bond linking a fragment of a serine proteinase to its serpin inhibitor Biochemistry 1998 37, N 18:6375–6379.
[68] Ibarra C. A., Blouse G. E., Christian T. D., Shore J. D. The contribution of the exosite residues of plasminogen activator inhibitor-1 to proteinase inhibition J. Biol. Chem 2004 279, N 5:3643–3650.
[69] Tucker H. M., Gerard R. D. Sequence requirements in the reactive-center loop of plasminogen-activator inhibitor-1 for recognition of plasminogen activators Eur. J. Biochem 1996 237, N 1:180–187.
[70] Krisnamurti Ch., Alving B. Plasminogen activator inhibitor type 1: biochemistry and evidence for modulation of fibrinolysis in vivo Semin. Thromb. and Hemost 1992 18, N 1 P. 67–80.
[71] Lindahl T. L., Ohlsson P. I., Wiman B. The mechanism of the reaction between human plasminogen-activator inhibitor 1 and tissue plasminogen activator Biochem. J 1990 265, N 1:109–113.
[72] Gaussem P., Grailhe P., Angles-Cano E. Sodium dodecyl sulfate-induced dissociation of complexes between human tissue plasminogen activator and its specific inhibitor. J. Biol. Chem. 1993. 268, N 16:12150–12155.
[73] Stefansson S., Haudenschild C., Lawrence D. Beyond fibrinolysis: the role of plasminogen activator inhibitor and vitronectin in vascular wound healing Trends Cardiovascul. Med 1998 8, N 4:175–180.
[74] Debrock S., Declerck P. J. Neutralization of plasminogen activator inhibitor-1 inhibitory properties: identification of two different mechanisms Biochim. Biophys. Acta 1997 1337, N 2:257–266.
[75] Alessi M. C., Juhan-Vague J., Declerck P. J., Collen D. Molecular forms of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) in human plasma Thromb. Res 1991 62, N 4:275–285.
[76] Kjoller L., Martensen P. M., Sottrup-Jensen L., Justesen J., Rodenburg K. W., Andreasen P. A. Conformational changes of the reactive-centre loop and -strand 5 A accompany temperature-dependent inhibitor-substrate transition of plasminogen-activator inhibitor 1 Eur. J. Biochem 1996 241, N 1:38–46.
[77] Calugaru S. V., Swanson R., Olson S. T. The pH dependence of serpin-proteinase complex dissociation reveals a mechanism of complex stabilization involving inactive and active conformational states of the proteinase which are perturbable by calcium J. Biol. Chem 2001 276, N 35:32446–32455.
[78] Gettins P. G. The F-helix of serpins plays an essential, active role in the proteinase inhibition mechanism FEBS Lett 2002 523, N 1–3:2–6.
[79] Liu C. X., Li Y., Obermoeller-McCormick L. M., Schwartz A. L., Bu G. The putative tumor suppressor LRP1B, a novel member of the low density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein J. Biol. Chem 2001 276, N 31:28889–28896.
[80] Sakata Y., Loskutoff D. J., Gladson C. L. Mechanism of protein C dependent clot lysis role of plasminogen activator inhibitor. Blood. 1986; 68, N 6:1218–1223.
[81] Sakata Y., Curriden S., Lawrence D. Activated protein C stimulated the fibrinolytic activity Proc. Natl Acad. Sci. USA 1985 82, N 4:1121–1125.
[82] Rezaie A. R. Vitronectin function as a cofactor for rapid inhibition of activated protein C by plasminogen activator-inhibitor-1. Implification for the mechanisms of profibrinolytic action of protein C J. Biol. Chem 2001 276, N 19 P. 15567–15570.
[83] Sawaya R. Fibrinolysis and the central nervous system Philadelphia: Hanley and Belfus Inc., 1990 306 p.
[84] Deng G., Curriden S. A., Wang S., Rosenberg S., Loskutoff D. J. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J. Cell Biol 1996 134, N 6:1563–1571.
[85] Czekay R. P., Loskutoff D. J. Unexpected role of plasminogen activator inhibitor-1 in cell adhesion and detachment. Exp. Biol. Med. 2004; 229, N 11:1090–1096.
[86] Noel A., Maillard C., Rocks N., Jost M., Chabottaux V., Sounni N. E., Maquoi E., Cataldo D., Foidart J. M. Membrane associated proteases and their inhibitors in tumour angiogenesis J. Clin. Pathol 2004 57, N 6:577–584.
[87] Bajou K., Noel A., Gerard R. D., Masson V., Brunner N., Hols-Hansen C., Skobe M., Fusening N. E., Carmeliet P., Collen D., Foidart J. M. Absence of host plasminogen activator inhibitor-1 prevents cancer invasion and vascularisation Nat. Med 1998 4, N 8:923–928.
[88] Deng G., Curriden S. A., Hu G., Czekay R. P., Loskutoff D. J. Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin J. Cell Physiol 2001 198, N 1:23–33.
[89] Kamikubo Y., Neels J. G., Degryse B. Vitronectin inhibits plasminogen activator inhibitor-1 induced signaling and chemotaxis by blocking plasminogen activator inhibitor-1 binding to the low-density lipoprotein receptor-related protein Int. J. Biochem. Cell Biol 2009 41, N 3:578–585.
[90] Degryse B., Sier C. F. M., Resnati M., Conese M., Blasi F. PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor FEBS Lett 2001 505, N 2 P. 249–254.