Skip to main content
SpringerLink
Log in

A Brief Account of Structure-Function Relationship of the Traditional Cysteine Protease Inhibitor - Cystatin with a Special Focus on Human Family 1 and 2 Cystatins

  • Chapter
  • First Online:
Book cover Proteases in Physiology and Pathology

  • 1079 Accesses

Abstract

Cystatins are well-documented cysteine protease inhibitors with highly conserved structural folds, distributed in a variety of species. Involvement of cystatin in various biochemical pathways through regulation of protein degradation makes it an element of amazing therapeutic possibilities for treatment of a broad range of diseases. Cystatin superfamily has been divided into four groups: stefins or family 1; cystatins or family 2; kininogens or family 3; and family 4 cystatin. The cystatin superfamily shares a common cystatin fold constituting five antiparallel β-sheets enfolded around a five-turn α-helix forming a cuneus-shaped structure that blocks the access of the active site of papain-like cysteine proteases (CPs). Crystallographic and mutagenesis studies identify three conserved regions mainly involved in the interaction with papain (C1) family of CPs, namely, (a) N-terminal region, (b) L1 loop, and (c) L2 loop. Despite sharing the same structural fold and inhibiting through the same mechanism, cystatin demonstrates huge variation in inhibitory affinity toward C1 family of CPs. Relative contribution and sequential dissimilarity of three conserved sites controlled the diverse interaction patterns of cystatins, which in turn determined the wide-ranging affinity of cystatins toward papain family of CPs. Some of the members of family 2 cystatins show additional affinity toward legumain family of CPs through an alternate binding site compared to papains.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Barrett AJ, Fritz H, Grubb A et al (1986) Nomenclature and classification of the proteins homologous with the cysteine-proteinase inhibitor chicken cystatin. Biochem J 236:312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Müller-Esterl W, Fritz H, Kellermann J et al (1985) Genealogy of mammalian cysteine proteinase inhibitors. FEBS Lett 191:221–226

    Article  PubMed  Google Scholar 

  3. Abrahamson M, Alvarez-Fernandez M, Nathanson CM (2003) Cystatins. In Biochemical Society Symposia Portland Press Limited 70:179–199

    Article  CAS  Google Scholar 

  4. Turk V, Stoka V, Turk D (2008) Cystatins: biochemical and structural properties, and medical relevance. Front Biosci 13:5406–5420

    Article  CAS  PubMed  Google Scholar 

  5. Barrett AJ, Rawlings ND, Davies ME et al (1986) Cysteine proteinase inhibitors of cystatin superfamily. In: Barrett AJ, Rawlings ND (eds) Proteinase inhibitors Elsevier, Amsterdam, pp 519–569

    Google Scholar 

  6. Klotz C, Ziegler T, Daniłowicz-Luebert E, Hartmann S (2011) Cystatins of parasitic organisms. In: Cysteine proteases of pathogenic organisms. Springer US, New York, pp 208–221

    Google Scholar 

  7. Turk B, Turk D, Salvesen GS (2002) Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr Pharm Design 8:1623–1637

    Article  CAS  Google Scholar 

  8. Keppler D (2006) Towards novel anti-cancer strategies based on cystatin function. Cancer Lett 235:159–176

    Article  CAS  PubMed  Google Scholar 

  9. Revesz T, Ghiso J, Lashley T et al (2003) Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol 62:885–898

    Article  CAS  PubMed  Google Scholar 

  10. Joyce JA, Baruch A, Chehade K et al (2004) Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5:443–453

    Article  CAS  PubMed  Google Scholar 

  11. Mignatti P, Robbins E, Rifkin DB (1986) Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade. Cell 47:487–498

    Article  CAS  PubMed  Google Scholar 

  12. Coussens LM, Werb Z (1996) Matrix metal loproteinases and the development of cancer. Chem Biol 3:895–904

    Article  CAS  PubMed  Google Scholar 

  13. Dollery CM, McEwan JR, Henney AM (1995) Matrix metalloproteinases and cardiovascular disease. Circ Res 77:863–868

    Article  CAS  PubMed  Google Scholar 

  14. Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell 6:60–64

    CAS  Google Scholar 

  15. Turk V, Kos J, Turk B (2004) Cysteine cathepsins (proteases)—on the main stage of cancer? Cancer Cell 5:409–410

    Article  CAS  PubMed  Google Scholar 

  16. Yasuda Y, Kaleta J, Brömme D (2005) The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 57:973–993

    Article  CAS  PubMed  Google Scholar 

  17. Nakanishi H (2003) Neuronal and microglial cathepsins in aging and age-related diseases. Ageing Res Rev 2:367–381

    Article  CAS  PubMed  Google Scholar 

  18. Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S (2007) Cathepsin cysteine proteases in cardiovascular disease. FASEB J 21:3029–3041

    Article  CAS  PubMed  Google Scholar 

  19. Ochieng J, Chaudhuri G (2010) Cystatin superfamily. J Health Care Poor Underserved 21:51

    Article  PubMed  PubMed Central  Google Scholar 

  20. Turk V, Turk B (2008) Lysosomal cysteine proteases and their protein inhibitors: recent developments. Acta Chim Slov 55:727–738

    CAS  Google Scholar 

  21. Vasiljeva O, Reinheckel T, Peters C et al (2007) Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Design 13:387–403

    Article  CAS  Google Scholar 

  22. Fossum K, Whitaker JR (1968) Ficin and papain inhibitor from chicken egg white. Arch Biochem Biophys 125:367–375

    Article  CAS  PubMed  Google Scholar 

  23. Keilova H, Tomášek V (1974) Effect of papain inhibitor from chicken egg white on cathepsin B1. Biochim Biophys Acta 334:179–186

    Article  CAS  Google Scholar 

  24. Sen LC, Whitaker JR (1973) Some properties of a ficin-papain inhibitor from avion egg white. Arch Biochem Biophys 158:623–632

    Article  CAS  PubMed  Google Scholar 

  25. Turk V, Brzin J, Longer M et al (1983) Protein inhibitors of cysteine proteinases. III. Amino-acid sequence of cystatin from chicken egg white. H-S Z Physiol Chem 364:1487–1496

    Article  CAS  Google Scholar 

  26. Bode W, Engh R, Musil DJ et al (1988) The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. EMBO J 7:2593

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Barrett AJ (1981) Cystatin, the egg white inhibitor of cysteine proteinases. Methods Enzymol 80:771–778

    Article  CAS  Google Scholar 

  28. Grubb A, Löfberg H (1982) Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis. Proc Natl Acad Sci U S A 79:3024–3027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stubbs MT, Laber B, Bode W et al (1990) The refined 2.4 A X-ray crystal structure of recombinant human stefin B in complex with the cysteine proteinase papain: a novel type of proteinase inhibitor interaction. EMBO J 9:1939

    Google Scholar 

  30. Dayhoff MO, Barker WC, Hunt LT (1983) Establishing homologies in protein sequences. Methods Enzymol 91:524–545

    Article  CAS  PubMed  Google Scholar 

  31. Rawlings ND, Barrett AJ (1990) Evolution of proteins of the cystatin superfamily. J Mol Evol 30:60–71

    Article  CAS  PubMed  Google Scholar 

  32. Turk V, Bode W (1991) The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 285:213–219

    Article  CAS  PubMed  Google Scholar 

  33. Wood TC, Pearson WR (1999) Evolution of protein sequences and structures. J Mol Biol 291:977–995

    Article  CAS  PubMed  Google Scholar 

  34. Abrahamson M, Barrett A, Salvesen G, Grubb A (1986) Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem 261:11282–11289

    CAS  PubMed  Google Scholar 

  35. Kordiš D, Turk V (2009) Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes. BMC Evol Biol 9:1

    Article  CAS  Google Scholar 

  36. Turk B, Krizaj I, Kralj B (1993) Bovine stefin C, a new member of the stefin family. J Biol Chem 268:7323–7329

    CAS  PubMed  Google Scholar 

  37. Bjoerk I, Ylinenjaervi K (1992) Different roles of the two disulfide bonds of the cysteine proteinase inhibitor, chicken cystatin, for the conformation of the active protein. Biochemistry 31:8597–8602

    Article  CAS  Google Scholar 

  38. Paraoan L, Grierson I, Maden BE (2003) Fate of cystatin C lacking the leader sequence in RPE cells. Exp Eye Res 76:753–756

    Article  CAS  PubMed  Google Scholar 

  39. Ekström U, Wallin H, Lorenzo J (2008) Internalization of cystatin C in human cell lines. FEBS J 275:4571–4582

    Article  PubMed  CAS  Google Scholar 

  40. Wallin H, Bjarnadottir M, Vogel LK et al (2010) Cystatins–extra-and intracellular cysteine protease inhibitors: high-level secretion and uptake of cystatin C in human neuroblastoma cells. Biochimie 92:1625–1634

    Article  CAS  PubMed  Google Scholar 

  41. Ni J, Abrahamson M, Zhang M et al (1997) Cystatin E is a novel human cysteine proteinase inhibitor with structural resemblance to family 2 cystatins. J Biol Chem 272:10853–10858

    Article  CAS  PubMed  Google Scholar 

  42. Isemura S, Saitoh E, Sanada K, Minakata K (1991) Identification of full-sized forms of salivary (type) cystatins (cystatin SN, cystatin SA, cystatin S, and two phosphorylated forms of cystatin S) in human whole saliva and determination of phosphorylation sites of cystatin S. J Biochem 110:648–654

    Article  CAS  PubMed  Google Scholar 

  43. Ryan CM, Souda P, Halgand F et al (2010) Confident assignment of intact mass tags to human salivary cystatins using top-down Fourier-transform ion cyclotron resonance mass spectrometry. J Am Soc Mass Spectrom 21:908–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dickinson DP (2002) Salivary (SD-type) cystatins: over one billion years in the making—but to what purpose? Crit Rev Oral Biol Med 13:485–508

    Article  CAS  PubMed  Google Scholar 

  45. Veillard F, Lecaille F, Lalmanach G (2008) Lung cysteine cathepsins: intruders or unorthodox contributors to the kallikrein–kinin system? Int J Biochem Cell Biol 40:1079–1094

    Article  CAS  PubMed  Google Scholar 

  46. Cadena RA, Colman RW (1991) Structure and functions of human kininogens. Trends Pharmacol Sci 12:272–275

    Article  Google Scholar 

  47. Kakizuka A, Kitamura N, Nakanishi S (1988) Localization of DNA sequences governing alternative mRNA production of rat kininogen genes. J Biol Chem 263:3884–3892

    CAS  PubMed  Google Scholar 

  48. Kitamura N, Kitagawa H, Fukushima D et al (1985) Structural organization of the human kininogen gene and a model for its evolution. J Biol Chem 260:8610–8617

    CAS  PubMed  Google Scholar 

  49. Müller-Esterl W, Iwanaga S, Nakanishi S (1986) Kininogens revisited. Trends Biochem Sci 11:336–339

    Article  Google Scholar 

  50. Turk B, Stoka V, Björk I et al (1995) High-affinity binding of two molecules of cysteine proteinases to low-molecular-weight kininogen. Protein Sci 4:1874–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Turk B, Stoka V, Turk V et al (1996) High-molecular-weight kininogen binds two molecules of cysteine proteinases with different rate constants. FEBS Lett 391:109–112

    Article  CAS  PubMed  Google Scholar 

  52. Salvesen G, Parkes C, Abrahamson M et al (1986) Human low-Mr kininogen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. Biochem J 234:429–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Reynolds JL, Skepper JN, McNair R et al (2005) Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol 16:2920–2930

    Article  CAS  PubMed  Google Scholar 

  54. Jones AL, Hulett MD, Parish CR (2005) Histidine-rich glycoprotein: a novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Immunol Cell Biol 83:106–118

    Article  CAS  PubMed  Google Scholar 

  55. Brown WM, Dziegielewska KM (1997) Friends and relations of the cystatin superfamily—new members and their evolution. Protein Sci 6:5–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cornwall GA, Cameron A, Lindberg I et al (2003) The cystatin-related epididymal spermatogenic protein inhibits the serine protease prohormone convertase 2. Endocrinology 144:901–908

    Article  CAS  PubMed  Google Scholar 

  57. Valente RH, Dragulev B, Perales J et al (2001) BJ46a, a snake venom metalloproteinase inhibitor. Eur J Biochem 268:3042–3052

    Article  CAS  PubMed  Google Scholar 

  58. Rawlings ND, Tolle DP, Barrett AJ (2004) Evolutionary families of peptidase inhibitors. Biochem J 378:705–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rawlings ND, Waller M, Barrett AJ, Bateman A (2014) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 42:D503–D509

    Article  CAS  PubMed  Google Scholar 

  60. Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 40:D343–D350

    Article  CAS  PubMed  Google Scholar 

  61. Nei M, Rooney AP (2005) Concerted and birth-and-death evolution of multigene families. Annu Rev Genet 39:121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cornwall GA, Hsia N (2003) A new subgroup of the family 2 cystatins. Mol Cell Endocrinol 200:1–8

    Article  CAS  PubMed  Google Scholar 

  63. Aagaard A, Listwan P, Cowieson N et al (2005) An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: relationship to cystatins and the tumor suppressor TIG1. Structure 13:309–317

    Article  CAS  PubMed  Google Scholar 

  64. Dixelius J, Olsson AK, Thulin Å et al (2006) Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res 66:2089–2097

    Article  CAS  PubMed  Google Scholar 

  65. Zhu S (2008) Did cathelicidins, a family of multifunctional host-defense peptides, arise from a cysteine protease inhibitor? Trends Microbiol 16:353–360

    Article  CAS  PubMed  Google Scholar 

  66. Bennett CS, Khorshid HR, Kitchen JA et al (2004) Characterization of the human secreted phosphoprotein 24 gene (SPP2) and comparison of the protein sequence in nine species. Matrix Biol 22:641–651

    Article  CAS  PubMed  Google Scholar 

  67. Toroian D, Price PA (2008) The essential role of fetuin in the serum-induced calcification of collagen. Calcif Tissue Int 82:116–126

    Article  CAS  PubMed  Google Scholar 

  68. Blaydon DC, Nitoiu D, Eckl KM et al (2011) Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion. Am J Hum Genet 89:564–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Parker BS, Ciocca DR, Bidwell BN et al (2008) Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer. J Pathol 214:337–346

    Article  CAS  PubMed  Google Scholar 

  70. Vasilopoulos Y, Walters K, Cork MJ et al (2008) Association analysis of the skin barrier gene cystatin A at the PSORS5 locus in psoriatic patients: evidence for interaction between PSORS1 and PSORS5. Eur J Hum Genet 16:1002–1009

    Article  CAS  PubMed  Google Scholar 

  71. Vasilopoulos Y, Cork MJ, Teare D et al (2007) A nonsynonymous substitution of cystatin A, a cysteine protease inhibitor of house dust mite protease, leads to decreased mRNA stability and shows a significant association with atopic dermatitis. Allergy 62:514–519

    Article  CAS  PubMed  Google Scholar 

  72. Riccio M, Di Giaimo R, Pianetti S et al (2001) Nuclear localization of cystatin B, the cathepsin inhibitor implicated in myoclonus epilepsy (EPM1). Exp Cell Biol 262:84–94

    Article  CAS  Google Scholar 

  73. Alakurtti K, Weber E, Rinne R et al (2005) Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations. Eur J Hum Genet 13:208–215

    Article  CAS  PubMed  Google Scholar 

  74. Žerovnik E, Pompe-Novak M, Škarabot M et al (2002) Human stefin B readily forms amyloid fibrils in vitro. Biochim Biophys Acta 1594:1–5

    Article  PubMed  Google Scholar 

  75. Lalioti MD, Mirotsou M, Buresi C et al (1997) Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). Am J Hum Genet 60:342

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Abrahamson M (1988) Human cysteine proteinase inhibitors: isolation, physiological importance, inhibitory mechanism, gene structure and relation to hereditary cerebral hemorrhage. Scand J Clin Lab Invest 48:21–31

    Article  Google Scholar 

  77. Sanchez JC, Guillaume E, Lescuyer P et al (2004) Cystatin C as a potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease. Proteomics 4:2229–2233

    Article  CAS  PubMed  Google Scholar 

  78. Nilsson J, Rüetschi U, Halim A et al (2009) Enrichment of glycopeptides for glycan structure and attachment site identification. Nat Methods 6:809–811

    Article  CAS  PubMed  Google Scholar 

  79. Chen JM, Dando PM, Rawlings ND et al (1997) Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem 272:8090–8098

    Article  CAS  PubMed  Google Scholar 

  80. Snorradottir AO (2006) Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects. Brain Pathol 16:55–59

    Article  PubMed  Google Scholar 

  81. Zurdel J, Finckh U, Menzer G et al (2002) CST3 genotype associated with exudative age related macular degeneration. Br J Ophthalmol 86:214–219

    Article  PubMed  PubMed Central  Google Scholar 

  82. Freije JP, Abrahamson M, Olafsson I et al (1991) Structure and expression of the gene encoding cystatin D, a novel human cysteine proteinase inhibitor. J Biol Chem 266:20538–20543

    CAS  PubMed  Google Scholar 

  83. Balbin M, Hall A, Grubb A et al (1994) Structural and functional characterization of two allelic variants of human cystatin D sharing a characteristic inhibition spectrum against mammalian cysteine proteinases. J Biol Chem 269:23156–23162

    CAS  PubMed  Google Scholar 

  84. Cappello F, Gatti E, Camossetto V et al (2004) Cystatin F is secreted, but artificial modification of its C-terminus can induce its endocytic targeting. Exp Cell Biol 297:607–618

    Article  CAS  Google Scholar 

  85. Langerholc T, Zavašnik-Bergant V, Turk B et al (2005) Inhibitory properties of cystatin F and its localization in U937 promonocyte cells. FEBS J 272:1535–1545

    Article  CAS  PubMed  Google Scholar 

  86. Nathanson CM, Wasselius J, Wallin H, Abrahamson M (2002) Regulated expression and intracellular localization of cystatin F in human U937 cells. Eur J Biochem 269:5502–5511

    Article  CAS  PubMed  Google Scholar 

  87. Hashimoto SI, Suzuki T, Nagai S et al (2000) Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression. Blood 96:2206–2214

    CAS  PubMed  Google Scholar 

  88. Ni J, Fernandez MA, Danielsson L et al (1998) Cystatin F is a glycosylated human low molecular weight cysteine proteinase inhibitor. J Biol Chem 273:24797–24804

    Article  CAS  PubMed  Google Scholar 

  89. Obata-Onai A, Hashimoto SI, Onai N et al (2002) Comprehensive gene expression analysis of human NK cells and CD8+ T lymphocytes. Int Immunol 14:1085–1098

    Article  CAS  PubMed  Google Scholar 

  90. Halfon S, Ford J, Foster J et al (1998) Leukocystatin, a new class II cystatin expressed selectively by hematopoietic cells. J Biol Chem 273:16400–16408

    Article  CAS  PubMed  Google Scholar 

  91. Schüttelkopf AW, Hamilton G, Watts C, van Aalten DM (2006) Structural basis of reduction-dependent activation of human cystatin F. J Biol Chem 281:16570–16575

    Article  PubMed  CAS  Google Scholar 

  92. Zeeuwen PL, Vlijmen-Willems V, Egami H, Schalkwijk J (2002) Cystatin M/E expression in inflammatory and neoplastic skin disorders. Br J Dermatol 147:87–94

    Article  CAS  PubMed  Google Scholar 

  93. Zeeuwen PL, van Vlijmen-Willems IM, Jansen BJ et al (2001) Cystatin M/E expression is restricted to differentiated epidermal keratinocytes and sweat glands: a new skin-specific proteinase inhibitor that is a target for cross-linking by transglutaminase. J Invest Dermatol 116:693–701

    Article  CAS  PubMed  Google Scholar 

  94. Sotiropoulou G, Anisowicz A, Sager R (1997) Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer. J Biol Chem 272:903–910

    Article  CAS  PubMed  Google Scholar 

  95. Cheng T, Hitomi K, van Vlijmen-Willems IM et al (2006) Cystatin M/E is a high affinity inhibitor of cathepsin v and cathepsin l by a reactive site that is distinct from the legumain-binding site a novel clue for the role of cystatin m/e in epidermal cornification. J Biol Chem 281:15893–15899

    Article  CAS  PubMed  Google Scholar 

  96. Dickinson DP, Thiesse M, Hicks MJ (2002) Expression of type 2 cystatin genes CST1-CST5 in adult human tissues and the developing submandibular gland. DNA Cell Biol 21:47–65

    Article  CAS  PubMed  Google Scholar 

  97. Isemura S, Saitoh E, Ito S et al (1984) Cystatin S: a cysteine proteinase inhibitor of human saliva. J Biochem 96:1311–1314

    Article  CAS  PubMed  Google Scholar 

  98. Eliyahu E, Shtraizent N, He X et al (2011) Identification of cystatin SA as a novel inhibitor of acid ceramidase. J Biol Chem 286:35624–35633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Isemura S, Saitoh E, Sanada K (1986) Characterization of a new cysteine proteinase inhibitor of human saliva, cystatin SN, which is immunologically related to cystatin S. FEBS Lett 198:145–149

    Article  CAS  PubMed  Google Scholar 

  100. Jiang J, Liu HL, Liu ZH et al (2015) Identification of cystatin SN as a novel biomarker for pancreatic cancer. Tumor Biol 36:3903–3910

    Article  CAS  Google Scholar 

  101. Nagata K, Kudo N, Abe K et al (2000) Three-dimensional solution structure of oryzacystatin-I, a cysteine proteinase inhibitor of the rice, Oryza sativa L japonica. Biochemistry 39:14753–14760

    Article  CAS  PubMed  Google Scholar 

  102. Dieckmann T, Mitschang L, Hofmann M et al (1993) The structures of native phosphorylated chicken cystatin and of a recombinant unphosphorylated variant in solution. J Mol Biol 234:1048–1059

    Article  CAS  PubMed  Google Scholar 

  103. Engh RA, Dieckmann T, Bode W (1993) Conformational variability of chicken cystatin: comparison of structures determined by X-ray diffraction and NMR spectroscopy. J Mol Biol 234:1060–1069

    Article  CAS  PubMed  Google Scholar 

  104. Martin JR, Craven JC, Jerala R (1995) The three-dimensional solution structure of human stefin A. J Mol Biol 246:331–343

    Article  CAS  PubMed  Google Scholar 

  105. Schechter I, Berger A (1967) On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 27:157–162

    Article  CAS  PubMed  Google Scholar 

  106. Berger A, Schechter I (1970) Mapping the active site of papain with the aid of peptide substrates and inhibitors. Philos Trans R Soc Lond Ser B Biol Sci 257:249–264

    Article  CAS  Google Scholar 

  107. Rzychon M, Chmiel D, Stec-Niemczyk J (2004) Modes of inhibition of cysteine proteases. Acta Biochim 51:861–873

    CAS  Google Scholar 

  108. Estrada S, Pavlova A, Björk I (1999) The contribution of N-terminal region residues of cystatin a (stefin a) to the affinity and kinetics of inhibition of papain, cathepsin B, and cathepsin L. Biochemistry 38:7339–7345

    Article  CAS  PubMed  Google Scholar 

  109. Estrada S, Raub-Segall E, Björk I, Olson ST (2000) The N-terminal region of cystatin A (stefin A) binds to papain subsequent to the two hairpin loops of the inhibitor. Demonstration of two-step binding by rapid-kinetic studies of cystatin A labeled at the N-terminus with a fluorescent reporter group. Protein Sci 9:2218–2224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nycander M, Estrada S, Mort JS et al (1998) Two-step mechanism of inhibition of cathepsin B by cystatin C due to displacement of the proteinase occluding loop. FEBS Lett 422:61–64

    Article  CAS  PubMed  Google Scholar 

  111. Pavlova A, Krupa JC, Mort JS et al (2000) Cystatin inhibition of cathepsin B requires dislocation of the proteinase occluding loop. Demonstration by release of loop anchoring through mutation of His110. FEBS Lett 487:156–160

    Article  CAS  PubMed  Google Scholar 

  112. Renko M, Požgan U, Majera D, Turk D (2010) Stefin A displaces the occluding loop of cathepsin B only by as much as required to bind to the active site cleft. FEBS J 277:4338–4345

    Article  CAS  PubMed  Google Scholar 

  113. Jenko S, Dolenc I, Gunčar G et al (2003) Crystal structure of Stefin a in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo-and exopeptidases. J Mol Biol 326:875–885

    Article  CAS  PubMed  Google Scholar 

  114. Baron AC, DeCarlo AA, Featherstone JD (1999) Functional aspects of the human salivary cystatins in the oral environment. Oral Dis 5:234–240

    Article  CAS  PubMed  Google Scholar 

  115. Bieth JG (1995) Theoretical and practical aspects of proteinase inhibition kinetics. Methods Enzymol 248:59

    Article  CAS  PubMed  Google Scholar 

  116. Mihelič M, Teuscher C, Turk V, Turk D (2006) Mouse stefins A1 and A2 (Stfa1 and Stfa2) differentiate between papain-like endo-and exopeptidases. FEBS Lett 580:4195–4199

    Article  PubMed  CAS  Google Scholar 

  117. Turk D, Gunčar G, Podobnik M, Turk B (1998) Revised definition of substrate binding sites of papain-like cysteine proteases. Biol Chem 379:137–148

    Article  CAS  PubMed  Google Scholar 

  118. Turk V, Stoka V, Vasiljeva O et al (2012) Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys 1824:68–88

    Article  CAS  Google Scholar 

  119. Auerswald EA, Nägler DK, Assfalg-Machleidt I et al (1995) Hairpin loop mutations of chicken cystatin have different effects on the inhibition of cathepsin B, cathepsin L and papain. FEBS Lett 361:179–184

    Article  CAS  PubMed  Google Scholar 

  120. Machleidt W, Thiele U, Assfalg-Machleidt I et al (1990) Molecular mechanism of inhibition of cysteine proteinases by their protein inhibitors: kinetic studies with natural and recombinant variants of cystatins and stefins. Biomed Biochim Acta 50:613–620

    Google Scholar 

  121. Machleidt W, Thiele U, Laber B et al (1989) Mechanism of inhibition of papain by chicken egg white cystatin. FEBS Lett 243:234–238

    Article  CAS  PubMed  Google Scholar 

  122. Hall A, Dalbøge H, Grubb A, Abrahamson M (1993) Importance of the evolutionarily conserved glycine residue in the N-terminal region of human cystatin C (Gly-11) for cysteine endopeptidase inhibition. Biochem J 291:123–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Abrahamson M, Mason RW, Hansson H et al (1991) Human cystatin C. Role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase. Biochem J 273:621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hall A, Håkansson K, Mason RW et al (1995) Structural basis for the biological specificity of cystatin C identification of leucine 9 in the n-terminal binding region as a selectivity-conferring residue in the inhibition of mammalian cysteine peptidases. J Biol Chem 270:5115–5121

    Article  CAS  PubMed  Google Scholar 

  125. Mason WR, Katia SC, Abrahamson M (1998) Amino acid substitutions in the N-terminal segment of cystatin C create selective protein inhibitors of lysosomal cysteine proteinases. Biochem J 330:833–838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pavlova A, Björk I (2003) Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases. Biochemistry 42:11326–11333

    Article  CAS  PubMed  Google Scholar 

  127. Baron AC, Gansky SA, Ryder MI, Featherstone JD (1999) Cysteine protease inhibitory activity and levels of salivary cystatins in whole saliva of periodontally diseased patients. J Periodontal Res 34:437–444

    Article  CAS  PubMed  Google Scholar 

  128. Blankenvoorde MF, Henskens YM, Van't Hof W et al (1996) Inhibition of the growth and cysteine proteinase activity of Porphyromonas gingivalis by human salivary cystatin S and chicken cystatin. Biol Chem Hoppe Seyler 377:847–850

    Article  CAS  Google Scholar 

  129. Bobek LA, Ramasubbu N, Wang X et al (1994) Biological activities and secondary structures of variant forms of human salivary cystatin SN produced in Escherichia coli. Gene 151:303–308

    Article  CAS  PubMed  Google Scholar 

  130. Saitoh E, Minaguchi K, Ishibashi O et al (1998) Production and characterization of two variants of human cystatin SA encoded by two alleles at theCST2Locus of the type 2 cystatin Gene family. Arch Biochem Biophys 352:199–206

    Article  CAS  PubMed  Google Scholar 

  131. Nishiura T, Ishibashi K, Abe K (1991) Isolation of three forms of cystatin from submandibular saliva of isoproterenol-treated rats, its properties and kinetic data. Biochim Biophys Acta 1077:346–354

    Article  CAS  PubMed  Google Scholar 

  132. Tseng CC, Tseng CP, Levine MJ, Bobek LA (2000) Differential effect toward inhibition of papain and cathepsin C by recombinant human salivary cystatin SN and its variants produced by a baculovirus system. Arch Biochem Biophys 380:133–140

    Article  CAS  PubMed  Google Scholar 

  133. Hall A, Ekiel I, Mason RW et al (1998) Structural basis for different inhibitory specificities of human cystatins C and D. Biochemistry 37:4071–4079

    Article  CAS  PubMed  Google Scholar 

  134. Shibuya K, Kaji H, Itoh T et al (1995) Human cystatin A is inactivated by engineered truncation. The NH2-terminal region of the cysteine proteinase inhibitor is essential for expression of its inhibitory activity. Biochemistry 34:12185–12192

    Article  CAS  PubMed  Google Scholar 

  135. Estrada S, Nycander M, Hill NJ et al (1998) The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L. Biochemistry 37:7551–7560

    Article  CAS  PubMed  Google Scholar 

  136. Pol E, Björk I (2003) Contributions of individual residues in the N-terminal region of cystatin B (stefin B) to inhibition of cysteine proteinases. Biochim Biophys 1645:105–112

    Article  CAS  Google Scholar 

  137. Pol E, Björk I (2001) Role of the single cysteine residue, Cys 3, of human and bovine cystatin B (stefin B) in the inhibition of cysteine proteinases. Protein Sci 10:1729–1738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Arai S, Watanabe H, Kondo H et al (1991) Papain-inhibitory activity of oryzacystatin, a rice seed cysteine proteinase inhibitor, depends on the central Gln-Val-Val-Ala-Gly region conserved among cystatin superfamily members. J Biochem 109:294–298

    CAS  PubMed  Google Scholar 

  139. Urwin PE, Atkinson HJ, McPherson MJ (1995) Involvement of the NH2-terminal region of oryzacystatin-I in cysteine proteinase inhibition. Protein Eng 8:1303–1307

    Article  CAS  PubMed  Google Scholar 

  140. Kouzuma Y, Tsukigata K, Inanaga H et al (2001) Molecular cloning and functional expression of cDNA encoding the cysteine proteinase inhibitor Sca from sunflower seeds. Biosci Biotechnol Biochem 65:969–972

    Article  CAS  PubMed  Google Scholar 

  141. Doi-Kawano K, Kouzuma Y, Yamasaki N, Kimura M (1998) Molecular cloning, functional expression, and mutagenesis of cDNA encoding a cysteine proteinase inhibitor from sunflower seeds. J Biochem 124:911–916

    Article  CAS  PubMed  Google Scholar 

  142. Auerswald EA, Genenger G, Assfalg-Machleidt I et al (1992) Recombinant chicken egg white cystatin variants of the QLVSG region. European J Biochem 209:837–845

    Article  CAS  Google Scholar 

  143. Björk I, Brieditis I, Raub-Segall E et al (1996) The importance of the second hairpin loop of cystatin C for proteinase binding. Characterization of the interaction of Trp-106 variants of the inhibitor with cysteine proteinases. Biochemistry 35:10720–10726

    Article  PubMed  Google Scholar 

  144. Hiltkel TR, Lee TC, Bobekl LA (1999) Structure/function analysis of human cystatin SN and comparison of the cysteine proteinase inhibitory profiles of human cystatins C and SN. J Dent Res 78:1401–1409

    Article  Google Scholar 

  145. Bedi GS, Zhou T, Bedi SK (1998) Production of rat salivary cystatin S variant polypeptides in Escherichia coli. Arch Oral Biol 43:173–182

    Article  CAS  PubMed  Google Scholar 

  146. Nikawa T, Towatari T, Ike Y, Katunuma N (1989) Studies on the reactive site of the cystatin superfamily using recombinant cystatin a mutants. FEBS Lett 255:309–314

    Article  CAS  PubMed  Google Scholar 

  147. Nycander M, Björk I (1990) Evidence by chemical modification that tryptophan-104 of the cysteine-proteinase inhibitor chicken cystatin is located in or near the proteinase-binding site. Biochem J 271:281–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Pavlova A, Estrada S, Björk I (2002) The role of the second binding loop of the cysteine protease inhibitor, cystatin a (stefin a), in stabilizing complexes with target proteases is exerted predominantly by Leu73. Eur J Biochem 269:5649–5658

    Article  CAS  PubMed  Google Scholar 

  149. Cimerman N, Prebanda MT, Turk B et al (1999) Interaction of cystatin C variants with papain and human cathepsins B, H and L. J Enzym Inhib 14:167–174

    Article  CAS  PubMed  Google Scholar 

  150. Pol E, Björk I (1999) Importance of the second binding loop and the C-terminal end of cystatin B (stefin B) for inhibition of cysteine proteinases. Biochemistry 38:10519–10526

    Article  CAS  PubMed  Google Scholar 

  151. Dall E, Fegg JC, Briza P, Brandstetter H (2015) Structure and mechanism of an Aspartimide-dependent peptide ligase in human Legumain. Angew Chem Int Edit 54:2917–2921

    Article  CAS  Google Scholar 

  152. Alvarez-Fernandez M, Barrett AJ, Gerhartz B et al (1999) Inhibition of mammalian legumain by some cystatins is due to a novel second reactive site. J Biol Chem 274:19195–19203

    Article  CAS  PubMed  Google Scholar 

  153. Baron AC, Barrett-Vespone NA, Featherstone JD (1999) Purification of large quantities of human salivary cystatins S, SA and SN: their interactions with the model cysteine protease papain in a non-inhibitory mode. Oral Dis 5:344–353

    Article  CAS  PubMed  Google Scholar 

  154. Benchabane M, Schlüter U, Vorster J et al (2010) Plant cystatins. Biochimie 92:1657–1666

    Article  CAS  PubMed  Google Scholar 

  155. Nandy SK, Bhuyan R, Seal A (2013) Modelling family 2 cystatins and their interaction with papain. J Biomol Struct Dyn 31:649–664

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

I would like to thank Dr. Alpana Seal, Retired Professor in Biophysics, Department of Biochemistry and Biophysics, University of Kalyani, for her help and encouragement. Thanks are also due to Bioinformatics Centre, University of Kalyani and Bioinformatics Centre, NEHU, Tura campus.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, 741235, India

    Suman K. Nandy

  2. Bioinformatics Infrastructure Facility (Bioinformatics Center), Department of Rural Development and Agricultural Production, North-Eastern Hill University, Tura Campus, Tura, Meghalaya, 794002, India

    Suman K. Nandy

Authors
  1. Suman K. Nandy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suman K. Nandy .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. St. Boniface Hospital Research Centre, University of Manitoba, Faculty of Health Sciences, College of Medicine, Institute of Cardiovascular Sciences, Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Nandy, S.K. (2017). A Brief Account of Structure-Function Relationship of the Traditional Cysteine Protease Inhibitor - Cystatin with a Special Focus on Human Family 1 and 2 Cystatins. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Physiology and Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-10-2513-6_27

Download citation

Publish with us

Policies and ethics

Search

Navigation