Skip to main content
SpringerLink
Log in

Evolution of proteins of the cystatin superfamily

  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Summary

We have examined the amino acid sequences of a number of proteins that have been suggested to be related to chicken cystatin, a protein from chicken egg white that inhibits cysteine proteinases. On the basis of statistical analysis, the following proteins were found to be members of the cystatin superfamily: human cystatin A, rat cystatin A(α), human cystatin B, rat cystatin B(β), rice cystatin, human cystatin C, ox colostrum cystatin, human cystatin S, human cystatin SA, human cystatin SN, chicken cystatin, puff adder cystatin, human kininogen, ox kininogen, rat kininogen, rat T-kininogens 1 and 2, human α2HS-glycoprotein, and human histidine-rich glycoprotein. Fibronectin is shown not to be a member of this superfamily, and the c-Ha-ras oncogene protein p21(Val-12) probably is not a member also. It was convenient to divide members of the superfamily into four types on the basis of the presence of one, two, or three copies of cystatin-like segments and the presence or absence of disulfide bonds. Evolutionary dendrograms were calculated by three methods, and from these we have constructed a scheme depicting the sequence of events in the evolution of these proteins. We suggest that about 1000 million years ago a precursor containing disulfide loops appeared, and that all disulfide-containing cystatins are derived from this. We follow the evolution of the proteins of the superfamily along four main lineages, with special attention to the part that duplication of segments has played in the development of the more complex molecules.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abe K, Emori Y, Kondo H, Suzuki K, Arai S (1987) Molecular cloning of a cysteine proteinase inhibitor of rice (oryzacystatin). J Biol Chem 262:16793–16797

    PubMed  Google Scholar 

  • Abe K, Emori Y, Kondo H, Arai S, Suzuki K (1988) The NH2-terminal 21 amino acid residues are not essential for the papain-inhibitory activity of oryzacystatin, a member of the cystatin superfamily. Expression of oryzacystatin cDNA and its truncated fragments inEscherichia coli. J Biol Chem 263: 7655–7659

    PubMed  Google Scholar 

  • Abrahamson M, Ritonia A, Brown MA, Grubb A, Machleidt W, Barrett AJ (1987) Identification of the probable inhibitory reactive sites of the cysteine proteinase inhibitors human cystatin C and chicken cystatin. J Biol Chem 262:9688–9694

    PubMed  Google Scholar 

  • Al-Hashim I, Dickinson DP, Levine MJ (1988) Purification, molecular cloning, and sequencing of salivary cystatin SA-I. J Biol Chem 263:9381–9387

    PubMed  Google Scholar 

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

    Google Scholar 

  • Barrett AJ (1985) The cystatins: small protein inhibitors of cysteine proteinases. In: Khairallah EA, Bond JS, Bird JWC (eds) Intracellular protein catabolism. Alan R Liss, New York, pp 105–116

    Google Scholar 

  • Barrett AJ (1986) An introduction to the proteinases. In: Barrett AJ, Salvesen G (eds) Proteinase inhibitors. Elsevier Science Publishers, Amsterdam, pp 3–22

    Google Scholar 

  • Barrett AJ (1987) The cystatins: a new class of peptidase inhibitors. Trends Biochem Sci 12:193–196

    Article  Google Scholar 

  • Barrett AJ, Fritz H, Grubb A, Isemura S, Järvinen M, Katunuma N, Macleidt W, Müller-Esterl W, Sasaki M, Turk V (1986a) Nomenclature and classification of the proteins homologous with the cysteine proteinase inhibitor chicken cystatin. Biochem J 236:312

    PubMed  Google Scholar 

  • Barrett AJ, Rawlings ND, Davies ME, Machleidt W, Salvesen G, Turk V (1986b) Cysteine proteinase inhibitors of the cystatin superfamily. In: Barrett AJ, Salvesen G (eds) Proteinase inhibitors. Elsevier Science Publications, Amsterdam, pp 515–569

    Google Scholar 

  • Barrett AJ, Buttle DJ, Mason RW (1988) Lysosomal cysteine proteinases. ISI Atlas Sci: Biochem 1:256–260

    Google Scholar 

  • Cole T, Inglis AS, Roxburgh CM, Howlett GJ, Schreiber G (1985) Major acute phase α1-protein of the rat is homologous to bovine kininogen and contains the sequence for bradykinin: its synthesis is regulated at the mRNA level. FEBS Lett 182: 57–61

    Article  PubMed  Google Scholar 

  • Dayhoff MO (1978) Survey of new data and computer methods of analysis. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation, Washington DC, pp 1–8

    Google Scholar 

  • Dayhoff MO, Barker WC, Hunt LT (1978a) Protein superfamilies. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation, Washington DC, pp 9–20

    Google Scholar 

  • Dayhoff MO, Schwartz RM, Orwitt BC (1978b) A model of evolutionary change in proteins. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation, Washington DC, pp 345–352

    Google Scholar 

  • Elzanowski A, Barker WC, Hunt LT, Seibel-Ross E (1988) Cystatin domains in alpha-2-HS-glycoprotein and fetuin. FEBS Lett 227:167–170

    Article  PubMed  Google Scholar 

  • Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783–791

    Google Scholar 

  • Fitch WM, Margoliash E (1967) Construction of phylogenetic trees. Science 155:279–284

    PubMed  Google Scholar 

  • Furuto-Kato S, Matsumoto A, Kitamura A, Nakanishi J (1985) Primary structures of the mRNA's encoding the rat precursors for bradykinin and T-kinin. Structural relationship of kininogens with major acute phase protein and α1-cysteine proteinase inhibitor. J Biol Chem 260:12054–12059

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Grubb A, Löfberg H (1985) Human γ-trace. Structure, function and clinical use of concentration measurements. Scan J Clin Lab Invest 45(suppl 177):7–13

    Google Scholar 

  • Grubb A, Löfberg H, Barrett AJ (1984) The disulphide bridges of human cystatin C (gamma-trace) and chicken cystatin. FEBS Lett 170:370–374

    Article  Google Scholar 

  • Hawke DH, Yuan PM, Wilson KJ, Hunkapiller MW (1987) Identification of a long form of cystatin from human saliva by rapid microbore hplc mapping. Biochem Biophys Res Commun 145:1248–1253

    Article  PubMed  Google Scholar 

  • Hirado M, Tsunasawa S, Sakiyama F, Niinobe M, Fujii S (1985) Complete amino acid sequence of bovine colostrum low-M r cysteine proteinase inhibitor. FEBS Lett 186:41–45

    Article  PubMed  Google Scholar 

  • Hiwasa T, Yokoyama S, Ha J-M, Nuguchi S, Sakiyama S (1987) c-Ha-ras gene products are potent inhibitors of cathepsins B and L. FEBS Lett 211:23–26

    Article  PubMed  Google Scholar 

  • Isemura S, Saitoh E, Sanada K (1984) Isolation and aminoacid sequence of SAP-1, an acidic protein of human whole saliva, and sequence homology with human γ-trace. J Biochem (Tokyo) 96:489–498

    Google Scholar 

  • 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  PubMed  Google Scholar 

  • Isemura S, Saitoh E, Sanada K (1987) Characterization and amino acid sequence of a new acidic cysteine proteinase inhibitor (cystatin SA) structurally closely related to cystatin S, from human whole saliva. J Biochem (Tokyo) 102:693–704

    Google Scholar 

  • Keil-Dlouha V, Planchenault T (1986) Potential proteolytic activity of human plasma fibronectin. Proc Natl Acad Sci USA 83:5377–5381

    PubMed  Google Scholar 

  • Keil-Dlouha V, Turk V (1988) Structural analogies between adhesive proteins and cysteine proteinase inhibitors. Biol Chem Hoppe-Seyler 369:199–204

    PubMed  Google Scholar 

  • Kellermann J, Lottspeich F, Henschen A, Müller-Esterl W (1986) Completion of the primary structure of human high-molecular-mass kininogen. The amino acid sequence of the entire heavy chain and evidence for its evolution by gene triplication. Eur J Biochem 154:471–478

    Article  PubMed  Google Scholar 

  • Kellermann J, Thelen C, Lottspeich F, Henschen A, Vogel R, Müller-Esterl W (1987) Arrangement of the disulphide bridges in human low-M r kininogen. Biochem J 247:15–21

    PubMed  Google Scholar 

  • Kitamura N, Takagaki Y, Furuto S, Tanaka T, Nawa H, Nakanishi S (1983) A single gene for bovine high molecular weight and low molecular weight kininogens. Nature 305:545–549

    Article  PubMed  Google Scholar 

  • Kitamura N, Kitagawa H, Fukushima D, Takagaki Y, Miyata T, Nakanishi S (1985) Structural organisation of the human kininogen gene and a model for its evolution. J Biol Chem 260:8610–8617

    PubMed  Google Scholar 

  • Koide T (1988) Human histidine-rich glycoprotein gene: evidence for evolutionary relatedness to cystatin supergene family. Throm Res Suppl VIII:91–97

    Article  Google Scholar 

  • Koide T, Odani S (1987) Histidine-rich glycoprotein is evolutionarily related to the cystatin superfamily. FEBS Lett 216: 17–21

    Article  PubMed  Google Scholar 

  • Koide T, Foster D, Yoshitake S, Davie EW (1986) Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequences of its cDNA. Biochemistry 25:2220–2225

    Article  PubMed  Google Scholar 

  • Lee C-C, Bowman BH, Yang F (1987) Human α2-HS-glycoprotein: the A and B chains with a connecting sequence are encoded by a single mRNA transcript. Proc Natl Acad Sci USA 84:4403–4407

    PubMed  Google Scholar 

  • Levinson AD (1986) Normal and activatedras oncogenes and their encoded products. Trends Genet 2:81–90

    Article  Google Scholar 

  • Lipman DJ, Pearson WR (1985) Rapid and sensitive protein similarity searches. Science 227:1435–1441

    PubMed  Google Scholar 

  • Machleidt W, Borchart U, Fritz H, Brzin J, Ritonja A, Turk V (1983) Protein inhibitors of cysteine proteinases. II. Primary structure of stefin, a cytosolic protein inhibitor of cysteine proteinases from human polymorphonuclear granulocytes. Hoppe-Seyler's Z Physiol Chem 364:1481–1486

    PubMed  Google Scholar 

  • Moreau T, Esnard F, Gutman N, Degand P, Gauthier F (1988) Cysteine-proteinase-inhibiting function of T kininogen and of its proteolytic fragments. Eur J Biochem 173:185–190

    Article  PubMed  Google Scholar 

  • Müller-Esterl W, Fritz H, Kellermann J, Lottspeich F, Machleidt W, Turk V (1985) Genealogy of mammalian cysteine proteinase inhibitors. Common evolutionary origin of stefins, cystatins and kininogens. FEBS Lett 191:221–226

    Article  PubMed  Google Scholar 

  • Nawa H, Kitamura N, Hirose T, Asai M, Inayama S, Nakanishi S (1983) Primary structures of bovine liver low molecular weight kininogen precursors and their mRNAs. Proc Natl Acad Sci USA 80:90–94

    PubMed  Google Scholar 

  • Needleman SB, Wunsch CD (1970) A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol 48:443–453

    Article  PubMed  Google Scholar 

  • Nei M (1987) Molecular evolutionary genetics. Columbia University Press, New York

    Google Scholar 

  • Ohkubo I, Kurachi K, Takasawa T, Shiokawa H, Sasaki M (1984) Isolation of a human cDNA for α2-thiol proteinase inhibitor and its identity with low molecular weight kininogen. Biochemistry 23:5691–5697

    Article  PubMed  Google Scholar 

  • Ritonja A, Machleidt W, Barrett AJ (1985) Amino acid sequence of the intracellular cysteine proteinase inhibitor cystatin B from human liver. Biochem Biophys Res Commun 131:1187–1192

    Article  PubMed  Google Scholar 

  • Ritonja A, Evans HJ, Machleidt W, Barrett AJ (1987) Amino acid sequence of cystatin from venom of the African puff adder (Bitis arietans). Biochem J 246:799–802

    PubMed  Google Scholar 

  • Saitoh E, Isemura S, Sanada K, Kim H-S, Smithies O, Maeda N (1988) Cystatin superfamilies. Evidence that family II cystatin genes are evolutionarily related to family III cystatin genes. Biol Chem Hoppe-Seyler 369:191–197

    PubMed  Google Scholar 

  • Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    PubMed  Google Scholar 

  • Sali A, Turk V (1987) Prediction of the secondary structures of stefins and cystatins, the low molecular mass protein inhibitors of cysteine proteinases. Biol Chem Hoppe-Seyler 368: 493–499

    PubMed  Google Scholar 

  • Salvesen G, Parkes C, Abrahamson M, Grubb A, Barrett AJ (1986) Human low molecular weight 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

    PubMed  Google Scholar 

  • Schopf JW, Hayes JM, Walter MR (1983) Evolution of Earth's earliest ecosystems: recent progress and unresolved problems. In: Schopf JW (ed) Earth's earliest biosphere: its origin and evolution. Princeton University Press, Princeton NJ, pp 361–384

    Google Scholar 

  • Schwabe C, Anastasi A, Crow H, McDonald JK, Barrett AJ (1984) Cystatin amino acid sequence and possible secondary structure. Biochem J 217:813–817

    PubMed  Google Scholar 

  • Sokal RR, Michener CD (1958) A statistical method for evaluating systematic relationships. Univ Kans Sci Bull 28:1409–1438

    Google Scholar 

  • Sueyoshi T, Miyata T, Kato H, Iwanaga S (1984) Disulfide bonds in bovine HMW kininogens. Seikagaku 56:808

    Google Scholar 

  • Sueyoshi T, Enjyoji K-I, Shimada T, Kato H, Iwanaga S, Bando Y, Kominami E, Katunuma N (1985) A new function of kininogens as thiol-proteinase inhibitors: inhibition of papain and cathepsins B, H and L by bovine, rat and human plasma kininogens. FEBS Lett 181:193–195

    Article  Google Scholar 

  • Takagaki Y, Kitamura N, Nakanishi S (1985) Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens. Primary structures of two human prekininogens. J Biol Chem 260:8601–8609

    PubMed  Google Scholar 

  • Takio K, Kominami E, Wakamatsu N, Katunurna N, Titani K (1983) Amino acid sequence of rat liver thiol proteinase inhibitor. Biochem Biophys Res Commun 115:902–908

    Article  PubMed  Google Scholar 

  • Takio K, Kominami E, Bando Y, Katunuma N, Titani K (1984) Amino acid sequence of rat epidermal thiol proteinase inhibitor. Biochem Biophys Res Commun 121:149–154

    PubMed  Google Scholar 

  • Turk V, Brzin J, Longer M, Ritonja A, Eropkin M (1983) Protein inhibitors of cysteine proteinases. III. Amino-acid sequence of cystatin from chicken egg white. Hoppe-Seyler's Z Physiol Chem 364:1487–1496

    PubMed  Google Scholar 

  • Williams J (1982) The evolution of transferrin. Trends Biochem Sci 7:394–397

    Article  Google Scholar 

  • Yoshioka Y, Gejyo F, Marti T, Rickli EE, Bürgi W, Offner GD, Troxler RF, Schmid K (1986) The complete amino acid sequence of the A-chain of human plasma α2HS-glycoprotein. J Biol Chem 261:1665–1676

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Strangeways Research Laboratory, Worts Causeway, CB1 4RN, Cambridge, UK

    Neil D. Rawlings & Alan J. Barrett

Authors
  1. Neil D. Rawlings
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan J. Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rawlings, N.D., Barrett, A.J. Evolution of proteins of the cystatin superfamily. J Mol Evol 30, 60–71 (1990). https://doi.org/10.1007/BF02102453

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02102453

Key words

Search

Navigation