Serpin structure, function and dysfunction

Journal of Thrombosis and Haemostasis

Volumn 9, Issue 1 S, 2011, Pages 26-34

  Huntington, J A ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

Antithrombin; Crystallography; Haemostasis; Heparin; Polymerisation

Indexed keywords

ALPHA 1 ANTITRYPSIN; ANTITHROMBIN; ANTITHROMBIN III; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 9A; CALCIUM; CHICKEN OVALBUMIN UPSTREAM PROMOTER TRANSCRIPTION FACTOR; HEPARIN; PLASMINOGEN ACTIVATOR INHIBITOR 3; PROTEIN C; SERINE PROTEINASE INHIBITOR;

BINDING AFFINITY; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; DEACYLATION; ENZYME ACTIVITY; HEMOSTASIS; HUMAN; POLYMERIZATION; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN STRUCTURE; PROTEINASE INHIBITION; REVIEW; SIGNAL TRANSDUCTION;

HUMANS; MODELS, MOLECULAR; SERPINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79960638185     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/j.1538-7836.2011.04360.x     Document Type: Review

References (84)

1. Hunt LT, Dayhoff MO. A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor. Biochem Biophys Res Commun 1980; 95: 864-71.
2. Borsodi AD, Bradshaw RA, Rughani IK, Bruce RM. Structural and functional relationships of human antithrombin III and alpha-antitrypsin. Adv Exp Med Biol 1975; 52: 249-53.
3. Carrell R, Travis J. [alpha]1-Antitrypsin and the serpins: variation and countervariation. Trends Biochem Sci 1985; 10: 20-4.
4. Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC. An overview of the serpin superfamily. Genome Biol 2006; 7: 216.
5. Rawlings ND, Tolle DP, Barrett AJ. Evolutionary families of peptidase inhibitors. Biochem J 2004; 378: 705-16.
6. Schechter I, Berger A. On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 1967; 27: 157-62.
7. Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW. Crystal structure of ovalbumin as a model for the reactive centre of serpins. Nature 1990; 347: 99-102.
8. Im H, Ahn HY, Yu MH. Bypassing the kinetic trap of serpin protein folding by loop extension. Protein Sci 2000; 9: 1497-502.
9. Kaslik G, Kardos J, Szabo E, Szilagyi L, Zavodszky P, Westler WM, Markley JL, Graf L. Effects of serpin binding on the target proteinase: global stabilization, localized increased structural flexibility, and conserved hydrogen bonding at the active site. Biochemistry 1997; 36: 5455-64.
10. Stein PE, Tewkesbury DA, Carrell RW. Ovalbumin and angiotensinogen lack serpin S-R conformational change. Biochem J 1989; 262: 103-7.
11. Hood DB, Huntington JA, Gettins PG. Alpha 1-proteinase inhibitor variant T345R. Influence of P14 residue on substrate and inhibitory pathways. Biochemistry 1994; 33: 8538-47.
12. Engh RA, Huber R, Bode W, Schulze AJ. Divining the serpin inhibition mechanism: a suicide substrate 'springe'? Trends Biotechnol 1995; 13: 503-10.
13. Lawrence DA, Ginsburg D, Day DE, Berkenpas MB, Verhamme IM, Kvassman JO, Shore JD. Serpin-protease complexes are trapped as stable acyl-enzyme intermediates. J Biol Chem 1995; 270: 25309-12.
14. Wilczynska M, Fa M, Karolin J, Ohlsson PI, Johansson LB, Ny T. Structural insights into serpin-protease complexes reveal the inhibitory mechanism of serpins. Nat Struct Biol 1997; 4: 354-7.
15. Stratikos E, Gettins PG. Formation of the covalent serpin-proteinase complex involves translocation of the proteinase by more than 70 A and full insertion of the reactive center loop into beta-sheet A. Proc Natl Acad Sci U S A 1999; 96: 4808-13.
16. Huntington JA, Read RJ, Carrell RW. Structure of a serpin-protease complex shows inhibition by deformation. Nature 2000; 407: 923-6.
17. Loebermann H, Tokuoka R, Deisenhofer J, Huber R. Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. J Mol Biol 1984; 177: 531-57.
18. Huber R, Bode W. Structural basis of the activation and action of trypsin. Acc Chem Res 1978; 11: 114-22.
19. Calugaru SV, Swanson R, Olson ST. 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: 32446-55.
20. Fredenburgh JC, Stafford AR, Weitz JI. Conformational changes in thrombin when complexed by serpins. J Biol Chem 2001; 276: 44828-34.
21. Bock PE, Olson ST, Bjork I. Inactivation of thrombin by antithrombin is accompanied by inactivation of regulatory exosite I. J Biol Chem 1997; 272: 19837-45.
22. Li W, Johnson DJ, Adams TE, Pozzi N, De Filippis V, Huntington JA. Thrombin inhibition by serpins disrupts exosite II. J Biol Chem 2010; 285: 38621-9.
23. Peterson FC, Gettins PG. Insight into the mechanism of serpin-proteinase inhibition from 2D [1H-15N] NMR studies of the 69kDa alpha 1-proteinase inhibitor Pittsburgh-trypsin covalent complex. Biochemistry 2001; 40: 6284-92.
24. Dementiev A, Dobo J, Gettins PG. Active site distortion is sufficient for proteinase inhibition by serpins: structure of the covalent complex of alpha1-proteinase inhibitor with porcine pancreatic elastase. J Biol Chem 2006; 281: 3452-7.
25. Rau JC, Beaulieu LM, Huntington JA, Church FC. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost 2007; 5 (Suppl. 1): 102-15.
26. Li W, Huntington JA. The heparin binding site of protein C inhibitor is protease-dependent. J Biol Chem 2008; 283: 36039-45.
27. Ehrlich HJ, Keijer J, Preissner KT, Gebbink RK, Pannekoek H. Functional interaction of plasminogen activator inhibitor type 1 (PAI-1) and heparin. Biochemistry 1991; 30: 1021-8.
28. Cunningham DD, Wagner SL, Farrell DH. Regulation of protease nexin-1 activity by heparin and heparan sulfate. Adv Exp Med Biol 1992; 313: 297-306.
29. Huang X, Rezaie AR, Broze GJ Jr, Olson ST. Heparin is a major activator of the anticoagulant serpin, protein Z-dependent protease inhibitor (ZPI). J Biol Chem 2011; 286: 8740-51.
30. Olson ST, Bjork I. Predominant contribution of surface approximation to the mechanism of heparin acceleration of the antithrombin-thrombin reaction. Elucidation from salt concentration effects. J Biol Chem 1991; 266: 6353-64.
31. Verhamme IM, Bock PE, Jackson CM. The preferred pathway of glycosaminoglycan-accelerated inactivation of thrombin by heparin cofactor II. J Biol Chem 2004; 279: 9785-95.
32. Olson ST, Swanson R, Raub-Segall E, Bedsted T, Sadri M, Petitou M, Herault JP, Herbert JM, Bjork I. Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems. Comparison with heparin and low-molecular-weight heparin. Thromb Haemost 2004; 92: 929-39.
33. Baglin TP, Carrell RW, Church FC, Esmon CT, Huntington JA. Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc Natl Acad Sci U S A 2002; 99: 11079-84.
34. Qi X, Loiseau F, Chan WL, Yan Y, Wei Z, Milroy LG, Myers RM, Ley SV, Read RJ, Carrell RW, Zhou A. Allosteric modulation of hormone release from thyroxine and corticosteroid binding-globulins. J Biol Chem 2011; 286: 16163-73.
35. Schreuder HA, de Boer B, Dijkema R, Mulders J, Theunissen HJ, Grootenhuis PD, Hol WG. The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions. Nat Struct Biol 1994; 1: 48-54.
36. Carrell RW, Stein PE, Fermi G, Wardell MR. Biological implications of a 3 A structure of dimeric antithrombin. Structure 1994; 2: 257-70.
37. Langdown J, Belzar KJ, Savory WJ, Baglin TP, Huntington JA. The critical role of hinge-region expulsion in the induced-fit heparin binding mechanism of antithrombin. J Mol Biol 2009; 386: 1278-89.
38. Futamura A, Gettins PG. Serine 380 (P14) → glutamate mutation activates antithrombin as an inhibitor of factor Xa. J Biol Chem 2000; 275: 4092-8.
39. Huntington JA, Gettins PG. Conformational conversion of antithrombin to a fully activated substrate of factor Xa without need for heparin. Biochemistry 1998; 37: 3272-7.
40. Huntington JA, Olson ST, Fan B, Gettins PG. Mechanism of heparin activation of antithrombin. Evidence for reactive center loop preinsertion with expulsion upon heparin binding. Biochemistry 1996; 35: 8495-503.
41. Johnson DJ, Langdown J, Li W, Luis SA, Baglin TP, Huntington JA. Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation. J Biol Chem 2006; 281: 35478-86.
42. Olson ST, Srinivasan KR, Bjork I, Shore JD. Binding of high affinity heparin to antithrombin III. Stopped flow kinetic studies of the binding interaction. J Biol Chem 1981; 256: 11073-9.
43. Schedin-Weiss S, Richard B, Olson ST. Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes. Arch Biochem Biophys 2010; 504: 169-76.
44. Skinner R, Chang WS, Jin L, Pei X, Huntington JA, Abrahams JP, Carrell RW, Lomas DA. Implications for function and therapy of a 2.9 A structure of binary-complexed antithrombin. J Mol Biol 1998; 283: 9-14.
45. Bray B, Lane DA, Freyssinet JM, Pejler G, Lindahl U. Anti-thrombin activities of heparin. Effect of saccharide chain length on thrombin inhibition by heparin cofactor II and by antithrombin. Biochem J 1989; 262: 225-32.
46. Rezaie AR. Calcium enhances heparin catalysis of the antithrombin-factor Xa reaction by a template mechanism. Evidence that calcium alleviates Gla domain antagonism of heparin binding to factor Xa. J Biol Chem 1998; 273: 16824-7.
47. Olson ST, Bjork I. Role of protein conformational changes, surface approximation and protein cofactors in heparin-accelerated antithrombin-proteinase reactions. Adv Exp Med Biol 1992; 313: 155-65.
48. Li W, Johnson DJ, Esmon CT, Huntington JA. Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol 2004; 11: 857-62.
49. Rezaie AR. Partial activation of antithrombin without heparin through deletion of a unique sequence on the reactive site loop of the serpin. J Biol Chem 2002; 277: 1235-9.
50. Langdown J, Johnson DJ, Baglin TP, Huntington JA. Allosteric activation of antithrombin critically depends upon hinge region extension. J Biol Chem 2004; 279: 47288-97.
51. Yang L, Manithody C, Olson ST, Rezaie AR. Contribution of basic residues of the autolysis loop to the substrate and inhibitor specificity of factor IXa. J Biol Chem 2003; 278: 25032-8.
52. Manithody C, Yang L, Rezaie AR. Role of basic residues of the autolysis loop in the catalytic function of factor Xa. Biochemistry 2002; 41: 6780-8.
53. Izaguirre G, Olson ST. Residues Tyr253 and Glu255 in strand 3 of beta-sheet C of antithrombin are key determinants of an exosite made accessible by heparin activation to promote rapid inhibition of factors Xa and IXa. J Biol Chem 2006; 281: 13424-32.
54. Izaguirre G, Zhang W, Swanson R, Bedsted T, Olson ST. Localization of an antithrombin exosite that promotes rapid inhibition of factors Xa and IXa dependent on heparin activation of the serpin. J Biol Chem 2003; 278: 51433-40.
55. Johnson DJ, Li W, Adams TE, Huntington JA. Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation. EMBO J 2006; 25: 2029-37.
56. Johnson DJ, Langdown J, Huntington JA. Molecular basis of factor IXa recognition by heparin-activated antithrombin revealed by a 1.7-A structure of the ternary complex. Proc Natl Acad Sci U S A 2010; 107: 645-50.
57. Olson ST, Chuang YJ. Heparin activates antithrombin anticoagulant function by generating new interaction sites (exosites) for blood clotting proteinases. Trends Cardiovasc Med 2002; 12: 331-8.
58. Carlstrom AS, Lieden K, Bjork I. Decreased binding of heparin to antithrombin following the interaction between antithrombin and thrombin. Thromb Res 1977; 11: 785-97.
59. Huntington JA. Shape-shifting serpins - advantages of a mobile mechanism. Trends Biochem Sci 2006; 31: 427-35.
60. Kaiserman D, Whisstock JC, Bird PI. Mechanisms of serpin dysfunction in disease. Expert Rev Mol Med 2006; 8: 1-19.
61. Gooptu B, Lomas DA. Conformational pathology of the serpins: themes, variations, and therapeutic strategies. Annu Rev Biochem 2009; 78: 147-76.
62. Devlin GL, Bottomley SP. A protein family under 'stress'- serpin stability, folding and misfolding. Front Biosci 2005; 10: 288-99.
63. Janciauskiene S. Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta 2001; 1535: 221-35.
64. Owen MC, Brennan SO, Lewis JH, Carrell RW. Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder. N Engl J Med 1983; 309: 694-8.
65. Mushunje A, Zhou A, Carrell RW, Huntington JA. Heparin-induced substrate behavior of antithrombin Cambridge II. Blood 2003; 102: 4028-34.
66. Belorgey D, Hagglof P, Karlsson-Li S, Lomas DA. Protein misfolding and the serpinopathies. Prion 2007; 1: 15-20.
67. Knaupp AS, Bottomley SP. Serpin polymerization and its role in disease - the molecular basis of alpha1-antitrypsin deficiency. IUBMB Life 2009; 61: 1-5.
68. Davies MJ, Lomas DA. The molecular aetiology of the serpinopathies. Int J Biochem Cell Biol 2008; 40: 1273-86.
69. Carrell RW, Lomas DA. Conformational disease. Lancet 1997; 350: 134-8.
70. Belorgey D, Irving JA, Ekeowa UI, Freeke J, Roussel BD, Miranda E, Perez J, Robinson CV, Marciniak SJ, Crowther DC, Michel CH, Lomas DA. Characterisation of serpin polymers in vitro and in vivo. Methods 2010; 53: 255-66.
71. Yu MH, Lee KN, Kim J. The Z type variation of human alpha 1-antitrypsin causes a protein folding defect. Nat Struct Biol 1995; 2: 363-7.
72. Takehara S, Zhang J, Yang X, Takahashi N, Mikami B, Onda M. Refolding and polymerization pathways of neuroserpin. J Mol Biol 2010; 403: 751-62.
73. Dafforn TR, Mahadeva R, Elliott PR, Sivasothy P, Lomas DA. A kinetic mechanism for the polymerization of alpha1-antitrypsin. J Biol Chem 1999; 274: 9548-55.
74. James EL, Whisstock JC, Gore MG, Bottomley SP. Probing the unfolding pathway of alpha1-antitrypsin. J Biol Chem 1999; 274: 9482-8.
75. Devlin GL, Chow MK, Howlett GJ, Bottomley SP. Acid denaturation of alpha1-antitrypsin: characterization of a novel mechanism of serpin polymerization. J Mol Biol 2002; 324: 859-70.
76. Huntington JA, Sendall TJ, Yamasaki M. New insight into serpin polymerization and aggregation. Prion 2009; 3: 12-4.
77. Huntington JA, Whisstock J. Molecular contortionism- on the physical limits of serpin loop-sheet polymers. Biol Chem 2010; 391: 973-82.
78. Yamasaki M, Sendall TJ, Harris LE, Lewis GM, Huntington JA. Loop-sheet mechanism of serpin polymerization tested by reactive center loop mutations. J Biol Chem 2010; 285: 30752-8.
79. Yamasaki M, Li W, Johnson DJ, Huntington JA. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature 2008; 455: 1255-8.
80. Ordonez A, Martinez-Martinez I, Corrales FJ, Miqueo C, Minano A, Vicente V, Corral J. Effect of citrullination on the function and conformation of antithrombin. FEBS J 2009; 276: 6763-72.
81. Elliott PR, Pei XY, Dafforn TR, Lomas DA. Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease. Protein Sci 2000; 9: 1274-81.
82. McCoy AJ, Pei XY, Skinner R, Abrahams JP, Carrell RW. Structure of beta-antithrombin and the effect of glycosylation on antithrombin's heparin affinity and activity. J Mol Biol 2003; 326: 823-33.
83. Herbert JM, Herault JP, Bernat A, Savi P, Schaeffer P, Driguez PA, Duchaussoy P, Petitou M. SR123781A, a synthetic heparin mimetic. Thromb Haemost 2001; 85: 852-60.
84. Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci U S A 1997; 94: 14683-8.