Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1984 Dec;81(23):7353–7357. doi: 10.1073/pnas.81.23.7353

Partial primary structure of human pregnancy zone protein: extensive sequence homology with human alpha 2-macroglobulin.

L Sottrup-Jensen, J Folkersen, T Kristensen, B F Tack
PMCID: PMC392144  PMID: 6209714

Abstract

Human pregnancy zone protein (PZP) is a major pregnancy-associated protein. Its quaternary structure (two covalently bound 180-kDa subunits, which are further non-covalently assembled into a tetramer of 720 kDa) is similar to that of human alpha 2-macroglobulin (alpha 2M). Here we show, from the results of complete or partial sequence determination of a random selection of 38 tryptic peptides covering 685 residues of the subunit of PZP, that PZP and alpha 2M indeed are extensively homologous. In the stretches of PZP sequenced so far, the degree of identically placed residues in the two proteins is 68%, indicating a close evolutionary relationship between PZP and alpha 2M. Although the function of PZP in pregnancy is largely unknown, its close structural relationship to alpha 2M suggests analogous proteinase binding properties and a potential for being taken up in cells by receptor-mediated endocytosis. In this regard our studies indicate a bait region in PZP significantly different from that present in alpha 2M. PZP could be the human equivalent of the acute-phase alpha-macroglobulins (e.g., rat alpha 2M and rabbit alpha 1M) described earlier.

Full text

PDF
7356

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andus T., Gross V., Tran-Thi T. A., Heinrich P. C. Synthesis of alpha 2-macroglobulin in rat hepatocytes and in a cell-free system. FEBS Lett. 1983 Jan 10;151(1):10–14. doi: 10.1016/0014-5793(83)80331-7. [DOI] [PubMed] [Google Scholar]
  2. BEATON G. H., SELBY A. E., VEEN M. J., WRIGHT A. M. Starch gel electrophoresis of rat serum proteins. II. Slow alpha 2-globulin and other serum proteins in pregnant, tumorbearing, and young rats. J Biol Chem. 1961 Jul;236:2005–2008. [PubMed] [Google Scholar]
  3. Belt K. T., Carroll M. C., Porter R. R. The structural basis of the multiple forms of human complement component C4. Cell. 1984 Apr;36(4):907–914. doi: 10.1016/0092-8674(84)90040-0. [DOI] [PubMed] [Google Scholar]
  4. Benjamin D. C., Weimer H. E. Synthesis of alpha-2-AP (acute phase) globulin of rat serum by the liver. Nature. 1966 Mar 5;209(5027):1032–1033. doi: 10.1038/2091032b0. [DOI] [PubMed] [Google Scholar]
  5. Bloth B., Chesebro B., Svehag S. E. Ultrastructural studies of human and rabbit alpha-M-globulins. J Exp Med. 1968 Apr 1;127(4):749–756. doi: 10.1084/jem.127.4.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bohn H. Detection, characterization and diagnostic significance of human pregnancy-associated glycoproteins. Blut. 1973 Mar;26(3):205–209. doi: 10.1007/BF01632365. [DOI] [PubMed] [Google Scholar]
  7. Bohn H., Horne C. H., Rittner C., Than G. N. Letter: Standardisation of nomenclature for pregnancy-associated alpha-2 glycoprotein. Lancet. 1975 Aug 23;2(7930):367–368. doi: 10.1016/s0140-6736(75)92812-3. [DOI] [PubMed] [Google Scholar]
  8. Bohn H. Nachweis und Charakterisierung von Schwangerschafts-proteinen in der menschlichen Placenta, sowie ihre quantitative immunologische Bestimmung im Serum schwangerer Frauen. Arch Gynakol. 1971 Oct 28;210(4):440–457. doi: 10.1007/BF01628222. [DOI] [PubMed] [Google Scholar]
  9. Bohn H., Winckler W. Isolierung und Charakterisierung des schwangerschafts-assoziierten alpha2-Glykoproteins (alpha2-PAG) Blut. 1976 Dec;33(6):377–388. doi: 10.1007/BF00996570. [DOI] [PubMed] [Google Scholar]
  10. COOPER D. W. A SERUM PROTEIN PRESENT IN PREGNANT WOMEN. Nature. 1963 Nov 30;200:892–892. doi: 10.1038/200892a0. [DOI] [PubMed] [Google Scholar]
  11. Campbell R. D., Gagnon J., Porter R. R. Amino acid sequence around the thiol and reactive acyl groups of human complement component C4. Biochem J. 1981 Nov 1;199(2):359–370. doi: 10.1042/bj1990359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DiScipio R. G., Smith C. A., Muller-Eberhard H. J., Hugli T. E. The activation of human complement component C5 by a fluid phase C5 convertase. J Biol Chem. 1983 Sep 10;258(17):10629–10636. [PubMed] [Google Scholar]
  13. Folkersen J., Teisner B., Ahrons S., Svehag S. E. Affinity chromatographic purification of the pregnancy zone protein. J Immunol Methods. 1978;23(1-2):117–125. doi: 10.1016/0022-1759(78)90115-1. [DOI] [PubMed] [Google Scholar]
  14. Folkersen J., Teisner B., Grunnet N., Grudzinskas J. G., Westergaard J. G., Hindersson P. Circulating levels of pregnancy zone protein: normal range and the influence of age and gender. Clin Chim Acta. 1981 Mar 5;110(2-3):139–145. doi: 10.1016/0009-8981(81)90343-0. [DOI] [PubMed] [Google Scholar]
  15. Ganrot K. 2 -acute phase globulin in rat serum. Purification, determination and interaction with trypsin. Biochim Biophys Acta. 1973 Jan 25;295(1):245–251. doi: 10.1016/0005-2795(73)90091-3. [DOI] [PubMed] [Google Scholar]
  16. Ganrot P. O., Bjerre B. Alpha-1-antitrypsin and alpha-2-macroglobulin concentration in serum during pregnancy. Acta Obstet Gynecol Scand. 1967;46(2):126–137. [PubMed] [Google Scholar]
  17. Gordon A. H. The alpha macroglobulins of rat serum. Biochem J. 1976 Dec 1;159(3):643–650. doi: 10.1042/bj1590643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. HEIM W. G. A rat serum protein related to reproduction, tissue synthesis and lactation. Nature. 1962 Feb 3;193:491–491. doi: 10.1038/193491a0. [DOI] [PubMed] [Google Scholar]
  19. Horne C. H., McLay A. L., Tavadia H. B., Carmichael I., Mallinson A. C., Laiwah A. A., Thomas M. A., MacSween R. N. Studies on pregnancy-associated globulin. Clin Exp Immunol. 1973 Apr;13(4):603–611. [PMC free article] [PubMed] [Google Scholar]
  20. Horne C. H., Thomson A. W., Towler C. M., MacMillan F. K., Gibb L. M. Relationship of pregnancy-associated alpha2-glycoprotein (alpha2-PAG) to peripheral blood leucocytes. Scand J Immunol. 1978;8(1):75–80. doi: 10.1111/j.1365-3083.1978.tb00498.x. [DOI] [PubMed] [Google Scholar]
  21. Horne C. H., Weir R. J., Howie P. W., Goudie R. B. Effect of combined oestrogen-progestogen oral contraceptives on serum-levels of alpha 2-macroglobulin, transferrin, albumin, and IgG. Lancet. 1970 Jan 10;1(7637):49–50. doi: 10.1016/s0140-6736(70)91841-6. [DOI] [PubMed] [Google Scholar]
  22. Hubbard W. J., Anderson B. D., Balber A. E., Praud G. M., Alomran A. M., Shenton B. K. Immunosuppression by human alpha 2-macroglobulin, a 3800 Mr peptide, and other derivatives. Ann N Y Acad Sci. 1983;421:332–339. doi: 10.1111/j.1749-6632.1983.tb18122.x. [DOI] [PubMed] [Google Scholar]
  23. Hubbard W. J., Hess A. D., Hsia S., Amos D. B. The effects of electrophoretically "slow" and "fast" alpha-2 macroglobulin on mixed lymphocyte cultures. J Immunol. 1981 Jan;126(1):292–299. [PubMed] [Google Scholar]
  24. Janatova J., Tack B. F. Fourth component of human complement: studies of an amine-sensitive site comprised of a thiol component. Biochemistry. 1981 Apr 28;20(9):2394–2402. doi: 10.1021/bi00512a005. [DOI] [PubMed] [Google Scholar]
  25. Kueppers F. Studies on the Xh antigen in human serum. Humangenetik. 1969;7(2):98–103. doi: 10.1007/BF00287073. [DOI] [PubMed] [Google Scholar]
  26. Lebreton de Vonne T., Mouray H. Isolement d'alpha 1 M et d'alpha-2 M du lapin et leur influence sur l'activité enzymatique de la trypsine. C R Acad Sci Hebd Seances Acad Sci D. 1968 Mar 4;266(10):1076–1079. [PubMed] [Google Scholar]
  27. Lin T. M., Halbert S. P., Kiefer D. Quantitative analysis of pregnancy-associated plasma proteins in human placenta. J Clin Invest. 1976 Feb;57(2):466–472. doi: 10.1172/JCI108298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lin T. M., Halbert S. P. Placental localization of human pregnancy--associated plasma proteins. Science. 1976 Sep 24;193(4259):1249–1252. doi: 10.1126/science.60782. [DOI] [PubMed] [Google Scholar]
  29. Lundgren E., Damber M. G., Roos G., von Schoultz B., Stigbrand T., Nilsson K., Alexander J. J. Cell lines with spontaneous secretion of pregnancy-associated alpha 2-globulin. Int J Cancer. 1979 Jul 15;24(1):45–48. doi: 10.1002/ijc.2910240108. [DOI] [PubMed] [Google Scholar]
  30. Mahoney W. C., Hermodson M. A. Separation of large denatured peptides by reverse phase high performance liquid chromatography. Trifluoroacetic acid as a peptide solvent. J Biol Chem. 1980 Dec 10;255(23):11199–11203. [PubMed] [Google Scholar]
  31. Morelis P., Ambrosioni J. C., Got R., Fontanges R. Observation au microscope électronique du complexe formé par l'alpha-1-macroglobuline de sérum de lapin avec la trypsine. C R Acad Sci Hebd Seances Acad Sci D. 1969 Oct 13;269(15):1453–1454. [PubMed] [Google Scholar]
  32. Mortensen S. B., Sottrup-Jensen L., Hansen H. F., Petersen T. E., Magnusson S. Primary and secondary cleavage sites in the bait region of alpha 2-macroglobulin. FEBS Lett. 1981 Dec 7;135(2):295–300. doi: 10.1016/0014-5793(81)80804-6. [DOI] [PubMed] [Google Scholar]
  33. Nagase H., Harris E. D., Jr, Woessner J. F., Jr, Brew K. Ovostatin: a novel proteinase inhibitor from chicken egg white. I. Purification, physicochemical properties, and tissue distribution of ovostatin. J Biol Chem. 1983 Jun 25;258(12):7481–7489. [PubMed] [Google Scholar]
  34. Nelles L. P., Schnebli H. P. Subunit structure of the rat alpha-macroglobulin proteinase inhibitors. Hoppe Seylers Z Physiol Chem. 1982 Jul;363(7):677–682. doi: 10.1515/bchm2.1982.363.2.677. [DOI] [PubMed] [Google Scholar]
  35. Ohlsson K. Isolation and partial characterization of two related trypsin binding alpha-macroglobulins of dog plasma. Biochim Biophys Acta. 1971 Apr 27;236(1):84–91. doi: 10.1016/0005-2795(71)90153-x. [DOI] [PubMed] [Google Scholar]
  36. SMITHIES O. Zone electrophoresis in starch gels and its application to studies of serum proteins. Adv Protein Chem. 1959;14:65–113. doi: 10.1016/s0065-3233(08)60609-9. [DOI] [PubMed] [Google Scholar]
  37. Sottrup-Jensen L., Petersen T. E., Magnusson S. A thiol-ester in alpha 2-macroglobulin cleaved during proteinase complex formation. FEBS Lett. 1980 Dec 1;121(2):275–279. doi: 10.1016/0014-5793(80)80361-9. [DOI] [PubMed] [Google Scholar]
  38. Sottrup-Jensen L., Stepanik T. M., Jones C. M., Lønblad P. B., Kristensen T., Wierzbicki D. M. Primary structure of human alpha 2-macroglobulin. I. Isolation of the 26 CNBr fragments, amino acid sequence of 13 small CNBr fragments, amino acid sequence of methionine-containing peptides, and alignment of all CNBr fragments. J Biol Chem. 1984 Jul 10;259(13):8293–8303. [PubMed] [Google Scholar]
  39. Sottrup-Jensen L., Stepanik T. M., Kristensen T., Wierzbicki D. M., Jones C. M., Lønblad P. B., Magnusson S., Petersen T. E. Primary structure of human alpha 2-macroglobulin. V. The complete structure. J Biol Chem. 1984 Jul 10;259(13):8318–8327. [PubMed] [Google Scholar]
  40. Starkey P. M., Barrett A. J. Evolution of alpha 2-macroglobulin. The demonstration in a variety of vertebrate species of a protein resembling human alpha 2-macroglobulin. Biochem J. 1982 Jul 1;205(1):91–95. doi: 10.1042/bj2050091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Stigbrand T., Damber M. G., von Schoultz B. Purification of the pregnancy zone protein by affinity chromatography. Acta Chem Scand B. 1978;B32(10):717–719. doi: 10.3891/acta.chem.scand.32b-0717. [DOI] [PubMed] [Google Scholar]
  42. Stimson W. H., Blackstock J. C. Synthesis of a pregnancy-associated alpha-macroglobulin by human leucocytes. Experientia. 1975 Mar 15;31(3):371–373. doi: 10.1007/BF01922593. [DOI] [PubMed] [Google Scholar]
  43. Stimson W. H., Eubank-Scott L. The isolation and partial characterisation of a new alpha-macroglobulin from human pregnancy serum. FEBS Lett. 1972 Jul 1;23(3):298–302. doi: 10.1016/0014-5793(72)80301-6. [DOI] [PubMed] [Google Scholar]
  44. Stimson W. H., Farquharson D. M. The molecular weight of pregnancy-associated alpha2-glycoprotein and its subunits. Int J Biochem. 1978;9(11):839–843. doi: 10.1016/0020-711x(78)90034-4. [DOI] [PubMed] [Google Scholar]
  45. Stimson W. H. Studies on the immunosuppressive properties of a pregnancy-associated alpha-macroglobulin. Clin Exp Immunol. 1976 Aug;25(2):199–206. [PMC free article] [PubMed] [Google Scholar]
  46. Stimson W. H. Transplantation--nature's success. Lancet. 1972 Mar 25;1(7752):684–684. doi: 10.1016/s0140-6736(72)90484-9. [DOI] [PubMed] [Google Scholar]
  47. Straube W., Klausch B., Hofmann R., Brock J. Immunchemische Untersuchungen zum Problem der "pregnancy zone". V. Nachweis und Verhalten schwangerschaftstypischer Proteine in Fraktionen aus Schwangeren-, Retroplacentar- und Nabelschnurserum. Arch Gynakol. 1972;212(3):230–245. doi: 10.1007/BF00673107. [DOI] [PubMed] [Google Scholar]
  48. Swenson R. P., Howard J. B. Amino acid sequence of the tryptic peptide containing the alkylamine-reactive site from human alpha 2-macroglobulin. Identification of gamma-glutamylmethylamide. J Biol Chem. 1980 Sep 10;255(17):8087–8091. [PubMed] [Google Scholar]
  49. Tack B. F., Harrison R. A., Janatova J., Thomas M. L., Prahl J. W. Evidence for presence of an internal thiolester bond in third component of human complement. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5764–5768. doi: 10.1073/pnas.77.10.5764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Than G. N., Csaba I. F., Szabó D. G., Karg N. J., Novák P. F. Quantitative Immunological study of pregnancy-associated alpha2-globulin antigen. Vox Sang. 1976;30(2):134–138. doi: 10.1111/j.1423-0410.1976.tb02803.x. [DOI] [PubMed] [Google Scholar]
  51. Von Schoultz B., Stigbrand T. Characterization of the "pregnancy zone protein" in relation to other alpha 2-globulins of pregnancy. Biochim Biophys Acta. 1974 Aug 8;359(2):303–310. doi: 10.1016/0005-2795(74)90229-3. [DOI] [PubMed] [Google Scholar]
  52. Von Schoultz B., Stigbrand T., Tärnvik A. Inhibition of PHA-induced lymphocyte stimulation by the pregnancy zone protein. FEBS Lett. 1973 Dec 15;38(1):23–26. doi: 10.1016/0014-5793(73)80503-4. [DOI] [PubMed] [Google Scholar]
  53. Weimer H. E., Benjamin D. C., Darcy D. A. Synthesis of the alpha-1-glycoprotein (Darcy) of rat serum by the liver. Nature. 1965 Dec 18;208(5016):1221–1222. doi: 10.1038/2081221a0. [DOI] [PubMed] [Google Scholar]
  54. Weimer H. E., Benjamin D. C. Immunochemical detection of an acute-phase protein in rat serum. Am J Physiol. 1965 Oct;209(4):736–744. doi: 10.1152/ajplegacy.1965.209.4.736. [DOI] [PubMed] [Google Scholar]
  55. Weström B. R. Identification and characterization of trypsin, chymotrypsin and elastase inhibitors in porcine serum. Hoppe Seylers Z Physiol Chem. 1979 Dec;360(12):1869–1878. doi: 10.1515/bchm2.1979.360.2.1869. [DOI] [PubMed] [Google Scholar]
  56. Weström B. R., Karlsson B. W., Ohlsson K. Immuno-cross-reactivity between alpha-macroglobulins from pig, dog, rat and man including human pregnancy-associated alpha 2-glycoprotein. Hoppe Seylers Z Physiol Chem. 1983 Apr;364(4):375–381. doi: 10.1515/bchm2.1983.364.1.375. [DOI] [PubMed] [Google Scholar]
  57. Wilding P., Adham N. F., Mehl J. W., Haverback B. J. Alpha-2-macroglobulin concentrations in human serum. Nature. 1967 Jun 17;214(5094):1226–1227. doi: 10.1038/2141226a0. [DOI] [PubMed] [Google Scholar]
  58. Zimmerman C. L., Pisano J. J. High-performance liquid chromatography of amino acid derivatives. Methods Enzymol. 1977;47:45–51. doi: 10.1016/0076-6879(77)47007-1. [DOI] [PubMed] [Google Scholar]
  59. von Schoultz B. A quantitative study of the pregnancy zone protein in the sera of pregnant and puerperal women. Am J Obstet Gynecol. 1974 Jul 15;119(6):792–797. doi: 10.1016/0002-9378(74)90092-1. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES