Summary
A computer-based statistical evaluation of the optimal alignments of the kringle domains of human plasminogen, human prothrombin, human tissue plasminogen activator, human urokinase, and human coagulation Factor XIIa, as well as the putative kringle of human haptoglobin, has been performed. A variety of different alignments has been examined and scores calculated in terms of the number of standard deviations (SD) of a given match from randomness. With the exception of human haptoglobin, it was found that very high alignment scores (8.9–23.0 SD from randomness) were obtained between each of the kringles, with the kringle 1 and kringle 5 regions of human plasminogen displaying the highest similarity, and the S kringle of human prothrombin and the human Factor XII kringle showing the least similarity. The relationships obtained were employed to construct an evolutionary tree for the kringles. The predicted alignments have also allowed nucleotide mutations in these regions to be evaluated more accurately. For those regions for which nucleotide sequences are known, we have employed the maximal alignments from the protein sequences to assess nucleotide sequence similarities. It was found that a range of approximately 40–55% of the nucleotide bases were placed at identical positions in the kringles, with the highest number found in the alignment of the two kringles of human tissue plasminogen activator and the lowest number in the alignment of the S kringle of prothrombin with the second kringle of tissue plasminogen activator. From both protein and nucleotide alignments, we conclude that haptoglobin is not statistically homologous to any other kringle.
Secondary structural comparisons of the kringle regions have been predicted by a combination of the Burgess and Chou-Fasman methods. In general, the kringles display a very high number of β-turns, and very low α-helical contents. From analysis of the predicted structures in relationship to the functional properties of these domains, it appears as though many of their functional differences can be related to possible conformational alterations resulting from amino acid substitutions in the kringles.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Burgess AW, Ponnuswamy PK, Scheraga HA (1974) Analysis of conformations of amino acid residues and prediction of backbone topography in proteins. Isr J Chem 12:239–286
Castellino FJ, Sator de Serrano V, Powell JR, Johnson WR, Beals JM (1986) Examination of the secondary structure of the kringle 4 domain of human plasminogen. Arch Biochem Biophys 247:312–320
Chou PY, Fasman GD (1978) Predictions of secondary structures of proteins from their amino acid sequence. Adv Enzymol 47:45–148
Cole KR, Castellino FJ (1984) The binding of antibibrinolytic amino acids to kringle 4-containing fragments of plasminogen. Arch Biochem Biophys 229:568–575
Dayhoff MO, Schwartz RM, Orcutt BC (1978) A model of evolutionary change in proteins. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 2. National Biomedical Research Foundation, Washington DC, pp 345–352
Degen SJF, MacGillivray RTA, Davie EW (1983) Characterization of the complementary deoxyribonucleic acid and gene coding for human prothrombin. Biochemistry 22:2087–2097
Gunzler WA, Steffens GJ, Otting F, Kim SA, Frankus E, Flohe L (1982) The primary structure of the high molecular mass urokinase from human urine. The complete amino acid sequence of the A-chain. Hoppe-Seyler's Z Physiol Chem 363: 1155–1165
Ichinose A, Takio K, Fujikawa K (1986) Localization of the binding site of tissue-type plasminogen activator to fibrin. J Clin Invest 78:163–169
Kurosky A, Barnett DR, Lee T-h, Touchstone B, Hay RE, Arnott MS, Bowman BH, Fitch WM (1980) Covalent structure of human haptoglobin: a serine protease homolog. Proc Natl Acad Sci USA 77:3388–3392
Lerch PG, Rickli EE, Lergier W, Gillessen D (1980) Localization of individual lysine binding regions in human plasminogen and investigations on their complex forming properties. Eur J Biochem 107:7–13
Magnusson S (1979) Thrombin and prothrombin. In: Blomback B, Hansen LA (eds) Plasma proteins. John Wiley & Sons, New York, pp 254–276
Magnusson S, Petersen TE, Sottrup-Jensen L, Clays, H (1975) Complete primary structure of prothrombin: isolation and reactivity of ten carboxylated glutamic residues and regulation of prothrombin activation by thrombin. In: Reich E, Rifkin DB, Shaw E (eds) Proteases and biological control. Cold Spring Harbor Press, New York, pp 123–149
Malinowski DP, Sadler JE, Davie EW (1984) Characterization of a complementary deoxyribonucleic acid coding for human and bovine plasminogen. Biochemistry 23:4243–4250
McMullen BA, Fujikawa K (1985) Amino acid sequence of the heavy chain of human alpha factor XIIa (activated Hageman Factor). J Biol Chem 260:5328–5334
Needleman SB, Wunsch CD (1970) A general method applicable to search for similarities in amino acid sequence of 2 proteins. J Mol Biol 48:443–453
Park CH, Tulinsky A (1986) Three dimensional structure of the kringle sequence: structure of prothrombin fragment 1. Biochemistry 25:3977–3982
Patthy L, Trexler M, Banyai L, Varadi A (1984) Kringles: modules specialized for protein binding. FEBS Lett 171:131–136
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 inEscherichia coli. Nature 301:214–221
Raugei G, Bensi G, Colantuoni V, Romano V, Santoro C, Costanzo F, Cortese R (1983) Sequence of human haptoglobin cDNA: evidence that the a and b subunits are coded by the same mRNA. Nucleic Acids Res 11:5811–1819
Rijken DC, Collen D (1981) Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J Biol Chem 256:7035–7041
Schwartz RM, Dayhoff MO (1979) 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 353–358
Sottrup-Jensen L, Claeys H, Petersen TE, Magnusson S (1978) The primary structure of human plasminogen: isolation and characterization of two lysine-binding fragments and one ‘mini’-plasminogen by elastase-catalyzed-specific limited proteolysis. In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC (eds) Fibrinolysis and thrombolysis, vol 3. Raven Press, New York, pp 191–209
Thorsen S (1975) Differences in binding to fibrin of native plasminogen and plasminogen modified by, proteolytic degradation. Influence of omega-carboxylic acids. Biochim Biophys Acta 393:55–65
Thorsen S, Glas-Greenwalt P, Astrup T (1972) Differences in binding to fibrin of urokinase and tissue plasminogen activator. Thromb Diath Haemorrh 28:65–74
Trexler M, Vali Z, Patthy L (1982) Structure of the e-amino caproic acid binding sites of human plasminogen. J Biol Chem 257:7401–7406
Verde P, Stoppelli MP, Galeffi P, DiNocera P, Blasi F (1984) Identification and primary sequence of an unspliced human urokinase poly(A)+RNA. Proc Natl Acad Sci USA 81:4727–4731
Wallen P, Bergsdorf N, Ranby M (1982) Purification and identification of 2 structural variants of porcine tissue plasminogen activator by affinity adsorption on fibrin. Biochim Biophys Acta 719:318–328
Walz DA, Hewett-Emmett D, Seegers WH (1977) Amino acid sequence of human prothrombin fragment-1 and fragment-2. Proc Natl Acad Sci USA 74:1969–1972
Wiman B, Collen D (1978) Molecular mechanism of physiological fibrinolysis. Nature 272:549–550
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Castellino, F.J., Beals, J.M. The genetic relationships between the kringle domains of human plasminogen, prothrombin, tissue plasminogen activator, urokinase, and coagulation factor XII. J Mol Evol 26, 358–369 (1987). https://doi.org/10.1007/BF02101155
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02101155