Abstract
The plasmin–antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α2-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α2-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α2-antiplasmin, the plasmin–antiplasmin system is also regulated by the general protease inhibitor α2-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.
Similar content being viewed by others
Abbreviations
- A2PI:
-
α2-Antiplasmin, α2-Plasmin inhibitor
- CHO:
-
Carbohydrate
- EGF-like:
-
Epidermal growth factor-like
- FN1:
-
Fibronectin type I
- K:
-
Kringle
- LBS:
-
Lysine binding site
- LMW:
-
Low molecular weight
- α2M:
-
α2-Macroglobulin
- NTP:
-
N-terminal peptide of Pgn
- PAI-1, -2:
-
Plasminogen activator inhibitor 1, 2
- Pgn:
-
Plasminogen
- Plm:
-
Plasmin
- RCL:
-
Reactive centre loop
- Serpin:
-
Serine protease inhibitor
- tPA:
-
Tissue-type plasminogen activator
- uPA:
-
Urokinase-type plasminogen activator
- uPAR:
-
Urokinase-type plasminogen activator receptor
References
Schaller J, Gerber S, Kämpfer U, Lejon S, Trachsel C (2008) Human blood plasma proteins: structure and function. Wiley, Chichester
Gerber SS (2009) The human α2-plasmin inhibitor: functional characterization of the unique plasmin(ogen)-binding region. Inaugural dissertation, University of Bern, Switzerland
Waisman DM (2003) Plasminogen: structure, activation, and regulation. Kluwer Academic/Plenum Publishers, New York
Syrovets T, Simmet T (2004) Novel aspects and new roles of the serine protease plasmin. Cell Mol Life Sci 61:873–885
Myöhänen H, Vaheri A (2004) Regulation and interaction in the activation of cell-associated plasminogen. Cell Mol Life Sci 61:2840–2858
Castellino FJ, Ploplis VA (2005) Structure and function of the plasminogen/plasmin system. Thromb Haemost 93:647–654
Raum D, Marcus G, Alper CA, Levey R, Taylor PD, Starzl TE (1980) Synthesis of human plasminogen by the liver. Science 208:1036–1037
Forsgren M, Råden B, Israelsson M, Larsson K, Hedén LO (1987) Molecular cloning and characterization of a full-length cDNA clone for human plasminogen. FEBS Lett 213:254–260
Murray JC, Buetow KH, Donovan M, Hornung S, Motulsky AG, Disteche C, Dyer K, Swisshelm K, Anderson J, Giblett E, Sadler E, Eddy R, Shows TB (1987) Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26–6q27. Am J Hum Genet 40:338–350
Petersen TE, Martzen MR, Ichinose A, Davie EW (1990) Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system. J Biol Chem 265:6104–6111
Ljinen HR, Hoylaerts M, Collen D (1980) Isolation and characterization of a human plasma protein with affinity for the lysine binding sites in plasminogen. J Biol Chem 255:10214–10222
Jones AL, Hulett MD, Altin JG, Hogg P, Parish CR (2004) Plasminogen is tethered with high affinity to the cell surface by the plasma protein, histidine-rich glycoprotein. J Biol Chem 279:38267–38276
Tordai H, Bányai L, Patthy L (1999) The PAN module: the N-terminal domains of plasminogen and hepatocyte growth factor are homologous with the apple domains of the prekallikrein family and with a novel domain found in numerous nematode proteins. FEBS Lett 461:63–67
Sottrup-Jensen L, Claeys H, Zajdel M, Petersen TE, Magnusson S (1978) The primary structure of human plasminogen: isolation of two lysine-binding fragments and one ‘mini-’ plasminogen (MW 38,000) by elastase-catalyzed-specific limited proteolysis. In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC (eds) Progress in chemical fibrinolysis and thrombolysis, vol 3. Raven Press, New York, pp 191–209
Wang X, Lin X, Loy JA, Tang J, Zhang XC (1998) Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. Science 281:1662–1665
Hayes ML, Castellino FJ (1979) Carbohydrate of the human plasminogen variants. I. Carbohydrate composition, glycopeptide isolation, and characterization. J Biol Chem 254:8768–8771
Hayes ML, Castellino FJ (1979) Carbohydrate of the human plasminogen variants. II. Structure of the asparagine-linked oligosaccharide unit. J Biol Chem 254:8772–8776
Hayes ML, Castellino FJ (1979) Carbohydrate of the human plasminogen variants. III. Structure of the O-glycosidically linked oligosaccharide unit. J Biol Chem 254:8777–8780
Marti T, Schaller J, Rickli EE, Schmid K, Kamerling JP, Gerwig GJ, van Halbeek H, Vliegenthart JFG (1988) The N- and O-linked carbohydrate chains of human, bovine and porcine plasminogen. Species specificity in relation to sialylation and fucosylation patterns. Eur J Biochem 173:57–63
Pirie-Sheperd SR, Stevens RD, Andon NL, Enghild JJ, Pizzo SV (1997) Evidence for a novel O-linked sialylated trisaccharide on Ser-248 of human plasminogen 2. J Biol Chem 272:7408–7411
Wang H, Prorok M, Bretthauer RK, Castellino FJ (1997) Serine-578 is a major phosphorylation locus in human plasma plasminogen. Biochemistry 36:8100–8116
Violand BN, Castellino FJ (1976) Mechanism of the urokinase-catalyzed activation of human plasminogen. J Biol Chem 251:3906–3912
Danø K, Andreasen PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L (1985) Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139–266
Robbins KC, Summaria L, Hsieh B, Shah RJ (1967) The peptide chains of human plasmin. Mechanism of activation of human plasminogen to plasmin. J Biol Chem 242:2333–2342
Wang X, Terzyan S, Tang J, Loy JA, Lin X, Zhang XC (2000) Human plasminogen catalytic domain undergoes an unusual conformational change upon activation. J Mol Biol 295:903–914
Schick LA, Castellino FJ (1974) Direct evidence for the generation of an active site in the plasminogen moiety of the streptokinase-human plasminogen activator complex. Biochem Biophys Res Commun 57:47–54
Kowalska-Loth B, Zakrzewski K (1975) The activation by staphylokinase of human plasminogen. Acta Biochim Pol 22:327–339
Ramesh V, Petros AM, Llinás M, Tulinsky A, Park CH (1987) Proton magnetic resonance study of lysine-binding to the kringle 4 domain of human plasminogen. The structure of the binding site. J Mol Biol 198:481–498
Mathews II, Vanderhoff-Hanavar P, Castellino FJ, Tulinsky A (1996) Crystal structures of the recombinant kringle 1 domain of human plasminogen in complexes with the ligands epsilon-aminocaproic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic acid. Biochemistry 35:2567–2576
Suenson E, Thorsen S (1981) Secondary-site binding of glu-plasmin, lys-plasmin and miniplasmin to fibrin. Biochem J 197:619–628
Wiman B, Lijnen HR, Collen D (1979) On the specific interaction between the lysine-binding sites in plasmin and complementary sites in alpha2-antiplasmin and in fibrinogen. Biochim Biophys Acta 579:142–154
Frank PS, Douglas JT, Locher M, Llinás M, Schaller J (2003) Structural/functional characterization of the α2-plasmin inhibitor C-terminal peptide. Biochemistry 42:1078–1085
Wang H, Yu A, Wiman B, Pap S (2003) Identification of amino acids in antiplasmin involved in its noncovalent ‘lysine-binding-site’-dependent interaction with plasmin. Eur J Biochem 270:2023–2029
Ponting CP, Marshall JM, Cederhoilm Williams SA (1992) Plasminogen: a structural review. Blood Coagul Fibrinolysis 3:605–614
Berg A, Sjöbring U (1993) PAM, a novel plasminogen-binding protein from Streptococcus pyogenes. J Biol Chem 268:25417–25424
Carlsson Wistedt A, Kotarsky H, Marti D, Ringdahl U, Castellino FJ, Schaller J, Sjöbring U (1998) Kringle 2 mediates high affinity binding of plasminogen to an internal sequence in streptococcal surface protein PAM. J Biol Chem 273:24420–24424
Miles LA, Dahlberg CM, Plow EF (1988) The cell binding domains of plasminogen and their function plasma. J Biol Chem 263:11928–11934
Marti D, Schaller J, Ochensberger B, Rickli EE (1994) Expression, purification and characterization of the recombinant kringle 2 and kringle 3 domains of human plasminogen and analysis of their binding affinities for ω-aminocarboxylic acids. Eur J Biochem 219:455–462
Söhndel S, Hu C-K, Marti D, Affolter M, Schaller J, Llinås M, Rickli EE (1996) Recombinant gene expression and 1H NMR characteristics of the kringle (2 + 3) supermodule: spectroscopic/functional individuality of plasminogen kringle domains. Biochemistry 35:2357–2364
Bürgin J, Schaller J (1999) Expression, isolation and characterization of a mutated human plasminogen kringle 3 with a functional lysine binding site. Cell Mol Life Sci 55:135–141
Marti DN, Hu C-K, An SSA, von Haller P, Schaller J, Llinás M (1997) Ligand preferences of kringle 2 and homologous domains of human plasminogen: canvassing weak, intermediate, and high-affinity binding sites by 1H-NMR. Biochemistry 36:11591–11604
Marti DN, Schaller J, Llinás M (1999) Solution structure and dynamics of the plasminogen kringle-2-AMCHA complex: 3(1)-helix in homologous domains. Biochemistry 38:15741–15755
Chang Y, Mochalkin I, McCance SG, Chen B, Tulinsky A, Castellino FJ (1998) Structure and ligand binding determinants of the recombinant kringle 5 domain of human plasminogen. Biochemistry 37:3258–3271
Gerber SS, Lejon S, Locher M, Schaller J (2010) The human α2-plasmin inhibitor: functional characterization of the unique plasmin(ogen)-binding region. Cell Mol Life Sci 67:1505–1518
Tranqui L, Prandini M-H, Chapel A (1979) The structure of plasminogen studied by electron microscopy. Biol Cellul 34:39–42
Weisel JW, Nagaswami C, Korsholm B, Petersen LC, Suenson E (1994) Interactions of plasminogen with polymerizing fibrin and its derivatives, monitored with a photoaffinity cross-linker and electron microscopy. J Mol Biol 235:1117–1135
Abad MC, Arni RK, Grella DK, Castellino FJ, Tulinsky A, Geiger JH (2002) The x-ray crystallographic structure of the angiogenesis inhibitor angiostatin. J Mol Biol 318:1009–1017
Walker JB, Nesheim ME (1999) The molecular weights, mass distribution, chain composition, and structure of soluble fibrin degradation products released from a fibrin clot perfused with plasmin. J Biol Chem 274:5201–5212
Mak TW, Rutledge G, Sutherland DJ (1976) Androgen-dependent fibrinolytic activity in a murine mammary carcinoma (Shionogi SC-115 cells) in vitro. Cell 7:223–226
Strickland S, Reich E, Sherman MI (1976) Plasminogen activator in early embryogenesis: enzyme production by trophoblast and parietal endoderm. Cell 9:231–240
Gross JL, Moscatelli D, Rifkin DB (1983) Increased capillary endothelial cell protease activity in response to angiogenic stimuli in vitro. Proc Natl Acad Sci U S A 80:2623–2627
Ossowski L, Reich E (1983) Antibodies to plasminogen activator inhibit human tumor metastasis. Cell 35:611–619
Nielsen LS, Kellerman GM, Behrendt N, Picone R, Danø K, Blasi F (1988) A 55,000–60,000 Mr receptor protein for urokinase-type plasminogen activator. Identification in human tumor cell lines and partial purification. J Biol Chem 263:2358–2363
Schäfer BM, Maier K, Eickhoff U, Todd RF, Kramer MD (1994) Plasminogen activation in healing human wounds. Am J Pathol 144:1269–1280
Netzel-Arnett S, Mitola DJ, Yamada SS, Chrysovergis K, Holmbeck K, Birkedal-Hansen H, Bugge TH (2002) Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. J Biol Chem 277:45154–45161
Bonnefoy A, Legrand C (2000) Proteolysis of subendothelial adhesive glycoproteins (fibronectin, thrombospondin, and von Willebrand factor) by plasmin, leukocyte cathepsin G, and elastase. Thromb Res 98:323–332
Nakagami Y, Abe K, Nishiyama N, Matsuki N (2000) Laminin degradation by plasmin regulates long-term potentiation. J Neurosci 20:2003–2010
Zeibdawi AR, Pryzdial EL (2001) Mechanism of factor Va inactivation by plasmin. Loss of A2 and A3 domains from a Ca2+-dependent complex of fragments bound to phospholipid. J Biol Chem 276:19929–19936
Hamilton KK, Fretto LJ, Grierson DS, McKee PA (1985) Effects of plasmin on von Willebrand factor multimers. Degradation in vitro and stimulation of release in vivo. J Clin Invest 76:261–270
Seligsohn U, Lubetsky A (2001) Genetic susceptibility to venous thrombosis. New Engl J Med 344:1222–1231
Ichinose A, Espling ES, Takamatsu J, Saito H, Shinmyozu K, Maruyama I, Petersen TE, Davie EW (1991) Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci U S A 88:115–119
Schuster V, Seregard S (2003) Ligneous conjunctivitis. Surv Ophthalmol 48:369–388
Levin EG (1983) Latent tissue plasminogen activator produced by human endothelial cells in culture: evidence for an enzyme-inhibitor complex. Proc Natl Acad Sci U S A 80:6804–6808
Sappino A-P, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, Vassalli J-D (1993) Extracellular proteolysis in the adult murine brain. J Clin Invest 92:679–685
Pfeiffer G, Schmidt M, Strube K-H, Geyer R (1989) Carbohydrate structure of recombinant human uterine tissue plasminogen activator expressed in mouse epithelial cells. Eur J Biochem 186:273–286
Harris RJ, Leonard CK, Guzzetta AW, Spellman MW (1991) Tissue plasminogen activator has an O-linked fucose attached to threoine-61 in the epidermal growth factor domain. Biochemistry 30:2311–2314
Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D (1983) Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301:214–221
Ny T, Elgh F, Lund B (1984) The structure of the human tissue-type plasminogen activator gene: correlation of introns and exon structures to functional and structural domains. Proc Natl Acad Sci U S A 81:5355–5359
Fisher R, Waller EK, Grossi G, Thompson D, Tizard R, Schleuning W-D (1985) Isolation and characterization of the human tissue-type plasminogen activator structural gene including its 5’ flanking region. J Biol Chem 260:11223–11230
Loscalzo J (1988) Structural and kinetic comparison of recombinant human single- and two-chain tissue plasminogen activator. J Clin Invest 82:1391–1397
Collen D, Lijnen HR (1991) Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 78:3114–3124
Byeon IJ, Llinás M (1991) Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid, an antifibrinolytic drug. J Mol Biol 222:1035–1051
de Vos AM, Ultsch MH, Kelley RF, Padmanabhan K, Tulinsky A, Westbrook ML, Kossiakoff AA (1992) Crystal structure of the kringle 2 domain of tissue plasminogen activator at 2.4 Å resolution. Biochemistry 31:270–279
Smith BO, Downing AK, Driscoll PC, Dudgeon TJ, Campbell ID (1995) The solution structure and backbone dynamics of the fibronectin type I and epidermal growth factor-like pair of modules of tissue-type plasminogen activator. Structure 3:823–833
Bennett WF, Paoni NF, Keyt BA, Botstein D, Jones AJ, Presta L, Wurm FM, Zoller MJ (1991) High resolution analysis of functional determinants on human tissue-type plasminogen activator. J Biol Chem 266:5191–5201
de Vries C, Vaerman H, Pannekoeck H (1989) Identification of the domains of tissue-type plasminogen activator involved in the augmented binding to fibrin after limited digestion with plasmin. J Biol Chem 264:12604–12610
Hoylaerts M, Rijken DC, Lijnen HR, Collen D (1982) Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 257:2912–2919
Lamba D, Bauer M, Huber R, Fischer S, Rudolph R, Kohnert U, Bode W (1996) The 2.3 Å crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator. J Mol Biol 258:117–135
Renatus M, Engh RA, Stubbs MT, Huber R, Fischer S, Kohnert U, Bode W (1997) Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA. EMBO J 16:4797–4805
Hajjar KA, Jacovina AT, Chacko J (1994) An endothelial cell receptor for plasminogen/tissue plasminogen activator I. Identity with annexin II. J Biol Chem 269:21191–21197
Cesarman GM, Guevara CA, Hajjar KA (1994) An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA) II. Annexin-II mediated enhancement of t-PA-dependent plasminogen activation. J Biol Chem 269:21198–21203
Hunt BJ, Segal H (1996) Hyperfibrinolysis. J Clin Pathol 49:958
Bernik MB, Kwaan HC (1969) Plasminogen activator activity in cultures from human tissues. An immunological and histochemical study. J Clin Invest 48:1740–1753
Duffy MJ (1990) Plasminogen activators and cancer. Blood Coagul Fibrinolysis 1:681–687
Nielsen LS, Hansen JG, Skriver L, Wilson EL, Kaltoft K, Zeuthen J, Danø K (1982) Purification of zymogen to plasminogen activator from human glioblastoma cells by affinity chromatography with monoclonal antibody. Biochemistry 21:6410–6415
Wun TC, Ossowski L, Reich E (1982) A proenzyme form of human urokinase. J Biol Chem 257:7262–7268
Buko AM, Kentzer EJ, Petros A, Menon G, Zuiderweg ERP, Sarin VK (1991) Characterization of posttranslational fucosylation in the growth factor domain of urinary plasminogen activator. Proc Natl Acad Sci U S A 88:3992–3996
Franco P, Iaccarino C, Chiaradonna F, Brandazza A, Iavarone C, Mastronicola MR, Nolli ML, Stoppelli MP (1997) Phosphorylation of human pro-urokinase on Ser138/303 impairs its receptor-dependent ability to promote myelomonocytic adherence and motility. J Cell Biol 137:779–791
Riccio A, Grimaldi G, Verde P, Sebastio G, Boast S, Blasi F (1985) The human urokinase-plasminogen activator gene and its promotor. Nucleic Acids Res 13:2759–2771
Kobayashi H, Schmitt M, Goretzki L, Chucholowski N, Calvete J, Kramer M, Günzler WA, Jänicke F, Graeff H (1991) Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA). J Biol Chem 266:5147–5152
Steffens GJ, Günzler WA, Otting F, Frankus E, Flohe L (1982) The complete amino acid sequence of low molecular mass urokinase from human urine. Hoppe Seylers Z Physiol Chem 363:1043–1058
Hansen AP, Petros AM, Meadows RP, Nettesheim DG, Mazar AP, Olejniczak ET, Xu RX, Pederson TM, Henkin J, Fesik SW (1994) Solution structure of the amino-terminal fragment of urokinase-type plasminogen activator. Biochemistry 33:4847–4864
Stephens RW, Bokman AM, Myohanen HT, Reisberg T, Tapiovaara H, Pedersen N, Grøndahl-Hansen J, Llinás M, Vaheri A (1992) Heparin binding to the urokinase kringle domain. Biochemistry 31:7572–7579
Li X, Bokman AM, Llinás M, Smith RA, Dobson CM (1994) Solution structure of the kringle domain from urokinase-type plasminogen activator. J Mol Biol 235:1548–1559
Appella E, Robinson EA, Ulrich SJ, Stoppelli MP, Corti A, Cassani G, Blasi F (1987) The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 262:4437–4440
Ploug M, Rahbek-Nielsen H, Ellis V, Roepstorff P, Danø K (1995) Chemical modification of the urokinase-type plasminogen activator and its receptor using tetranitromethane. Evidence for the involvement of specific tyrosine residues in both molecules during receptor-ligand interaction. Biochemistry 34:12524–12534
Katz BA, Sprengeler PA, Luong C, Verner E, Elrod K, Kritley M, Janc J, Spencer JR, Breitenbucher JG, Hui H, McGee D, Allen D, Martelli A, Mackman RL (2001) Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets. Chem Biol 8:1107–1121
Andreasen PA, Kjøller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22
Janciauskiene S (2001) Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta 1535:221–235
Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PGW, Irving IA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O’Donnell E, Salvesen GS, Travis J, Whisstock JC (2001) The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 276:33293–33296
Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC (2006) An overview of the serpin superfamily. Genome Biol 7:216–226
Gettins PG, Olson ST (2009) Exosite determinants of serpin specificity. J Biol Chem 284:20441–20445
Irving JA, Pike RN, Lesk AM, Whisstock JC (2000) Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res 10:845–864
van Gent D, Sharp P, Morgan K, Kalsheker N (2003) Serpins: structure, function and molecular evolution. Int J Biochem Cell Biol 35:1536–1547
Gettins PG (2000) Keeping the serpin machine running smoothly. Genome Res 10:1833–1835
Coughlin PB (2005) Antiplasmin: the forgotten serpin? FEBS J 272:4852–4857
Favier R, Aoki N, de Moerloose P (2001) Congenital α2-plasmin inhibitor deficiencies: a review. Br J Haematol 114:4–10
Saito H, Goodnough LT, Knowles BB, Aden DP (1982) Synthesis and secretion of α2-plasmin inhibitor by established human liver cell lines. Proc Natl Acad Sci U S A 79:5684–5687
Sumi Y, Ichikawa Y, Nakamura Y, Miura O, Aoki N (1989) Expression and characterization of pro α2-plasmin inhibitor. J Biochem 106:703–707
Ries M, Easton RL, Longstaff C, Zenker M, Morris HR, Dell A, Gaffney PJ (2002) Differences between neonates and adults in carbohydrate sequences and reaction kinetics of plasmin and α2-antiplasmin. Thromb Res 105:247–256
Locher M (2004) Strukturelle und funktionelle Untersuchungen am α2-Plasmininhibitor. Inaugural dissertation, University of Bern, Switzerland
Christensen S, Valnickova Z, Thøgersen IB, Olsen EH, Enghild JJ (1997) Assignment of a single disulphide bridge in human alpha2-antiplasmin: implications for the structural and functional properties. Biochem J 323:847–852
Hortin G, Fok KF, Toren PC, Strauss AW (1987) Sulfation of a tyrosine residue in the plasmin-binding domain of α2-antiplasmin. J Biol Chem 262:3082–3085
Hirosawa S, Nakamura Y, Miura O, Sumi Y, Aoki N (1988) Organization of the human alpha 2-plasmin inhibitor gene. Proc Natl Acad Sci U S A 85:6836–6840
Koyama T, Koike Y, Toyota S, Miyagi F, Suzuki N, Aoki N (1994) Different NH2-terminal form with 12 additional residues of α2-plasmin inhibitor from human plasma and culture media of Hep G2 cells. Biochem Biophys Res Commun 200:417–422
Lee KN, Jackson KW, Christiansen VJ, Chung KH, McKee PA (2004) A novel plasma proteinase potentiates α2-antiplasmin inhibition of fibrin digestion. Blood 103:3783–3788
Sasaki T, Morita T, Iwanaga S (1986) Identification of the plasminogen-binding site of human alpha 2-plasmin inhibitor. J Biochem 99:1699–1705
Clemmensen I, Thorsen S, Müllertz S, Petersen LC (1981) Properties of three different molecular forms of the α2plasmin inhibitor. Eur J Biochem 120:105–112
Kluft C, Los P, Jie AF, van Hinsbergh VW, Vellenga E, Jespersen J, Henny CP (1986) The mutual relationship between the two molecular forms of the major fibrinolysis inhibitor alpha-2-antiplasmin in blood. Blood 67:616–622
Holmes WE, Nelles L, Lijnen HR, Collen D (1987) Primary structure of human α2-antiplasmin, a serine protease inhibitor (serpin). J Biol Chem 262:1659–1664
Law RH, Sofian T, Kan WT, Horvath AJ, Hitchen CR, Langendorf CG, Buckle AM, Whisstock JC, Coughlin PB (2008) X-ray crystal structure of the fibrinolysis inhibitor alpha2-antiplasmin. Blood 111:2049–2052
Sakata Y, Aoki N (1982) Significance of cross-linking of α2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 69:536–542
Kimura S, Aoki N (1986) Cross-linking site in fibrinogen for α2-plasmin inhibitor. J Biol Chem 261:15591–15595
Wang H, Karlsson A, Sjöström I, Wiman B (2006) The interaction between plasminogen and antiplasmin variants as studied by surface plasmon resonance. Biochim Biophys Acta 1764:1730–1734
Christensen U, Clemmensen I (1977) Kinetic properties of the primary inhibitor of plasmin from human plasma. Biochem J 163:389–391
Wiman B, Collen D (1978) On the kinetics of the reaction between human antiplasmin and plasmin. Eur J Biochem 84:573–578
Wiman B, Collen D (1979) On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin. J Biol Chem 254:9291–9297
Wiman B, Boman L, Collen D (1978) On the kinetics of the reaction between human antiplasmin and a low-molecular-weight form of plasmin. Eur J Biochem 87:143–146
Potempa J, Shieh B-H, Travis J (1988) Alpha-2-antiplasmin: a serpin with two separate but overlapping reactive sites. Science 241:699–700
Miura O, Hirosawa S, Kato A, Aoki N (1989) Molecular basis for congenital deficiency of alpha-2-plasmin inhibitor: a frameshift mutation leading to elongation of the deduced amino acid sequence. J Clin Invest 83:1598–1604
Lind B, Thorsen S (1999) A novel missense mutation in the human plasmin inhibitor (alpha-2-antiplasmin) gene associated with a bleeding tendency. Br J Haematol 107:317–322
Sottrup-Jensen L (1989) α-Macroglobulins: structure, shape, and mechanisms of proteinase complex formation. J Biol Chem 264:11539–11542
Borth W (1992) α2-Macroglobulin, a multifunctional binding protein with targeting characteristics. FASEB J 6:3345–3353
Matthijs G, Devriendt K, Cassiman J-J, van den Berghe H, Marynen P (1992) Structure of the human alpha-2-macroglobulin gene and its promotor. Biochem Biophys Res Commun 184:596–603
Sottrup-Jensen L, Stepanik TM, Kristensen T, Wierzbicki DM, Jones CM, Lønblad PB, Magnusson S, Petersen TE (1984) Primary structure of human alpha-2-macroglobulin V. The complete structure. J Biol Chem 259:8318–8327
Jensen PE, Sottrup-Jensen L (1986) Primary structure of human alpha-2-macroglobulin. Complete disulfide bridge assignment and localization of two interchain bridges in the dimeric proteinase binding unit. J Biol Chem 261:15863–15869
Sottrup-Jensen L, Lønblad PB, Stepanik TM, Petersen TE, Magnusson S, Jörnvall H (1981) Primary structure of the ‘bait’ region for proteinases in α2-macroglobulin. FEBS Lett 127:167–173
Steiner JP, Migliorini M, Strickland DK (1987) Characterization of the reaction of plasmin with α2-macroglobulin: Effect of antifibrinolytic agents. Biochemistry 26:8487–8495
Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RCP, Perry R, Watson B Jr, Bassett SS, McInnis MG, Albert MS, Hyman BT, Tanzi RE (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 19:357–360
Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I (1997) Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 46:860–867
Pannekoek H, Veerman H, Lambers H, Diergaarde P, Verweij CL, van Zonneveld AJ, van Mourik JA (1986) Endothelial plasminogen activator inhibitor (PAI): a new member of the serpin gene family. EMBO J 5:2539–2544
Loskutoff DJ, Linders M, Keijer J, Veerman H, van Heerikhuizen H, Pannekoek H (1987) Structure of the human plasminogen activator inhibitor 1 gene: nonrandom distribution of introns. Biochemistry 26:3763–3768
Andreasen PA, Riccio A, Welinder KG, Douglas R, Sartorio R, Nielsen LS, Oppenheimer C, Blasi F, Danø K (1986) Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. FEBS Lett 209:213–218
Xue Y, Bjorquist P, Inghardt T, Linschoten M, Musil D, Sjolin L, Deinum J (1998) Interfering with the inhibitory mechanism of serpin: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide. Structure 6:627–636
Alessi MC, Declerck PJ, De Mol M, Nelles L, Collen D (1988) Purification and characterization of natural and recombinant human plasminogen activator inhibitor-1 (PAI-1). Eur J Biochem 175:531–540
Lawrence D, Strandberg L, Grundstrom T, Ny T (1989) Purification of active human plasminogen activator inhibitor 1 from Escherichia coli. Comparison with natural and recombinant forms purified from eukaryotic cells. Eur J Biochem 186:523–533
Keijer J, Linders M, Wegman JJ, Ehrlich HJ, Mertens K, Pannekoek H (1991) On the target specificity of plasminogen activator inhibitor 1: the role of heparin, vitronectin, and the reactive site. Blood 78:1254–1261
Heckman CM, Loskutoff DJ (1988) Bovine plasminogen activator inhibitor 1: specificity determinations and comparison of the active, latent, and guanidine-activated forms. Biochemistry 27:2911–2918
Sigurdardottir O, Wiman B (1994) Identification of a PAI-1 binding site in vitronectin. Biochim Biophys Acta 1208:104–110
Ehrlich AJ, Gebbbink RK, keijer J, Linders M, Preissner KT, Pannekoek H (1990) Alteration of serpin specificity by a protein cofactor. Vitronectin endows plasminogen activator inhibitor 1 with thrombin inhibitory properties. J Biol Chem 265:13029–13035
Erickson LA, Ginsberg MH, Loskutoff DJ (1984) Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 74:1465–1472
Juhan Vague I, Moerman B, De Cock F, Aillaud MF, Collen D (1984) Plasma levels of a specific inhibitor of tissue-type plasminogen activator (and urokinase) in normal and pathological conditions. Thromb Res 33:523–530
Fay WP, Parker AC, Condrey LR, Shapiro AD (1997) Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 90:204–208
Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B (1987) Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2:3–9
Medcalf RL, Stasinopoulos SJ (2005) The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J 272:4858–4867
Kruithof EKO, Baker MS, Bunn CL (1995) Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 86:4007–4024
Lecander I, Astedt B (1986) Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol 62:221–228
Kruithof EK, Vassalli JD, Schleuning WD, Mattaliano RJ, Bachmann F (1986) Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem 261:11207–11213
Schleuning WD, Medcalf RL, Hession C, Rothenbühler R, Shaw A, Kruithof EK (1987) Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester-mediated differentiation of U-937 human histiocytic lymphoma cells. Mol Cell Biol 7:4564–4567
Webb AC, Collins KL, Snyder SE, Alexander SJ, Rosenwasser LJ, Eddy RL, Shows TB, Auron PE (1987) Human monocyte Arg-Serpin cDNA. Sequence, chromosomal assignment, and homology to plasminogen activator-inhibitor. J Exp Med 166:77–94
Wohlwend A, Belin D, Vassalli JD (1987) Plasminogen activator-specific inhibitors produced by human monocytes/macrophages. J Exp Med 165:320–339
Dougherty KM, Pearson JM, Yang AY, Westrick RJ, Baker MS, Ginsburg D (1999) The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc Natl Acad Sci U S A 96:686–691
von Heijne G, Liljestrom P, Mikus P, Andersson H, Ny T (1991) The efficiency of the uncleaved secretion signal in the plasminogen activator inhibitor type 2 protein can be enhanced by point mutations that increase its hydrophobicity. J Biol Chem 266:15240–15243
Genton C, Kruithof EK, Schleuning WD (1987) Phorbol ester induces the biosynthesis of glycosylated and non-glycosylated plasminogen activator inhibitor 2 in high excess over urokinase-type plasminogen activator in human U-937 lymphoma cells. J Cell Biol 104:705–712
Belin D, Wohlwend A, Schleuning WD, Kruithof EK, Vassalli JD (1988) Facultative polypeptide translocation allows a single mRNA to encode the secreted and cytosolic forms of plasminogen activators inhibitor 2. EMBO J 8:3287–3294
Ye RD, Ahern SM, le Beau MM, Lebo RV, Sadler JE (1989) Structure of the gene for human plasminogen activator inhibitor-2. The nearest mammalian homologue of chicken ovalbumin. J Biol Chem 264:5495–5502
Samia JA, Alexander SJ, Horton KW, Auron PE, Byers MG, Shows TB Jr, Webb AC (1990) Chromosomal organization and localization of the human urokinase inhibitor gene: perfect structural conservation with ovalbumin. Genomics 6:159–167
Ye RD, Wun T-Z, Sadler JE (1987) cDNA cloning and expression in Escherichia coli of a plasminogen activator inhibitor from human placenta. J Biol Chem 262:3718–3725
Jensen PH, Schuler E, Woodrow G, Richardson M, Goss N, Hojrup P, Petersen TE, Rasmussen LK (1994) A unique interhelical insertion in plasminogen activator inhibitor-2 contains three glutamines, Gln83, Gln84, Gln86, essential for transglutaminase-mediated cross-linking. J Biol Chem 269:1594–1598
Ritchie H, Lawrie LC, Crombie PW, Mosesson MW, Booth NA (2000) Cross-linking of plasminogen activator inhibitor 2 and alpha(2)-antiplasmin to fibrin(ogen). J Biol Chem 275:24915–24920
Harrop SJ, Jankova L, Coles M, Jardine D, Whittaker JS, Gould AR, Meister A, Kung GC, Mabbutt BC, Curmi PM (1999) The crystal structure of plasminogen activator 2 at 2.0 Å resolution: implications for serpin function. Structure 7:43–54
Mikus P, Urano T, Liljestrom P, Ny T (1993) Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerizing SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms. Eur J Biochem 218:1071–1082
Miranda E, Lomas DA (2006) Neuroserpin: a serpin to think about. Cell Mol Life Sci 63:709–722
Galliciotti G, Sonderegger P (2006) Neuroserpin. Front Biosci 1:33–45
Yepes M, Lawrence DA (2004) Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. Thromb Haemost 91:457–464
Hastings GA, Coleman TA, Haudenschild CC, Stefansson S, Smith EP, Barthlow R, Cherry S, Sandkvist M, Lawerence DA (1997) Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. J Biol Chem 272:33062–33067
Schrimpf SP, Bleiker AJ, Brecevic L, Kozlov SV, Berger P, Osterwalder T, Krueger SR, Schinzel A, Sonderegger P (1997) Human neuroserpin (P12): cDNA cloning and chromosomal localization to 3q26. Genomics 40:55–62
Osterwalder T, Contartese J, Stoeckli ET, Kuhn TB, Sonderegger P (1996) Neuroserpin, an axonally secreted serine protease inhibitor. EMBO J 15:2944–2953
Yazaki M, Liepnieks JJ, Murrell JR, Takao M, Guenther B, Piccardo P, Farlow MR, Ghetti B, Benson MD (2001) Biochemical characterization of a neuroserpin variant associated with hereditary dementia. Am J Pathol 158:227–233
Ricagno S, Caccia S, Sorrentino G, Antonini G, Bolognesi M (2009) Human neuroserpin: structure and time-dependent inhibition. J Mol Biol 388:109–121
Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, Meins M, Sonderegger P (1998) The axonally secreted serine protease inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin. J Biol Chem 273:2312–2321
Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, Sonderegger P, Kinter J, Becker LM, Lacbawan F, Krasnewich D, Muenke M, Lawrence DA, Yerby MS, Shaw CM, Gooptu P, Elliott PR, Finch JT, Carrell RW, Lomas DA (1999) Familial dementia caused by polymerization of mutant neuroserpin. Nature 401:376–379
Eaton DL, Baker JB (1983) Evidence that a variety of cultured cells secrete protease nexin and produce a distinct cytoplasmic serine protease-binding factor. J Cell Physiol 117:175–182
Scott RW, Bergman BL, Bajpai A, Hersh RT, Rodriguez H, Jones BN, Barreda C, Watts S, Baker JB (1985) Protease nexin. Properties and a modified purification procedure. J Biol Chem 260:7029–7034
Nick H, Hofsteenge J, Shaw E, Rovelli G, Monard D (1990) Functional sites of glia-derived nexin (GDN): importance of the site reacting with the protease. Biochemistry 29:2417–2421
Carter RE, Cerosaletti KM, Burkin DJ, Fournier REK, Jones C, Greenberg BD, Citron BA, Festoff BW (1995) The gene for the serpin thrombin inhibitor (P17), protease nexin I, is located on human chromosome 2q33-q35 and on syntenic regions in the mouse and sheep genomes. Genomics 27:196–199
DeMeo DL, Mariani TJ, Lange C, Srisuma S, Litonjua AA, Celedon JC, lake SL, Reilly JJ, Chapman HA, Mecham BH, Haley KJ, Sylvia JS, Sparrow D, Spira AE, Beane J, Pinto-Plata V, Speizer FE, Shapiro SD, Weiss S, Silverman EK (2006) The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am J Hum Genet 78:253–264
Author information
Authors and Affiliations
Corresponding author
Additional information
The recommended names in the UniProt Knowledgebase (SwissProt and TrEMBL) were used. The protein structures are based on the coordinates deposited in the Protein Data Bank (PDB) and were visualized as well as rendered using the software PyMOL. If not stated otherwise, the standard rainbow colour representation was used.
Rights and permissions
About this article
Cite this article
Schaller, J., Gerber, S.S. The plasmin–antiplasmin system: structural and functional aspects. Cell. Mol. Life Sci. 68, 785–801 (2011). https://doi.org/10.1007/s00018-010-0566-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-010-0566-5