Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1978 Dec 1;148(6):1498–1509. doi: 10.1084/jem.148.6.1498

Mechanism of action of factor D of the alternative complement pathway

PMCID: PMC2185104  PMID: 82604

Abstract

Factor D (C3 proactivator convertase) of human serum has been shown to be absolutely necessary for alternative pathway function, for activation of the C3/C5 convertase of that pathway and not to be a subunit of this enzyme. Factor D was found to be present in human plasma in active form only, at a concentration of 2 microgram/ml, and not to be controlled by plasma protease inhibitors or by spontaneous decay. Unlike trypsin, factor D cleaves and activates factor B only when it is in Mg++-dependent complex with C3b, has no esterolytic activity, and is unable to cleave the B chain of insulin. The alleged functional and antigenic relationship of factor D to alpha-thrombin could not be verified. The results of this study led to the description of the mechanism of action of factor D in terms of the cryptic site hypothesis.

Full Text

The Full Text of this article is available as a PDF (756.9 KB).

Selected References

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

  1. Bolton A. E., Hunter W. M. The labelling of proteins to high specific radioactivities by conjugation to a 125I-containing acylating agent. Biochem J. 1973 Jul;133(3):529–539. doi: 10.1042/bj1330529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brade V., Bentley C., Bitter-Suermann D., Hadding U. Interaction of zymosan and of activated properdin with factor D-depleted guinea pig serum: implications for the mechanism of initial C3 cleavage via the alternative complement pathway. Z Immunitatsforsch Immunobiol. 1977 Feb;152(5):402–414. [PubMed] [Google Scholar]
  3. Brade V., Nicholson A., Bitter-Suermann D., Hadding U. Formation of the C3-cleaving properdin enzyme on zymosan. Demonstration that factor D is replaceable by proteolytic enzymes. J Immunol. 1974 Dec;113(6):1735–1743. [PubMed] [Google Scholar]
  4. Brade V., Nicholson A., Lee G. D., Mayer M. M. The reaction of zymosan with the properdin system: isolation of purified factor D from guinea pig serum and study of its reaction characteristics. J Immunol. 1974 May;112(5):1845–1854. [PubMed] [Google Scholar]
  5. Daha M. R., Fearon D. T., Austen K. F. Isolation of alternative pathway C3 convertase containing uncleaved B and formed in the presence of C3 nephritic factor (C3neF). J Immunol. 1976 Feb;116(2):568–570. [PubMed] [Google Scholar]
  6. David G. S., Reisfeld R. A. Protein iodination with solid state lactoperoxidase. Biochemistry. 1974 Feb 26;13(5):1014–1021. doi: 10.1021/bi00702a028. [DOI] [PubMed] [Google Scholar]
  7. Dieminger L., Vogt W., Lynen R. Purification and some properties of factor D of the human properdin system. Z Immunitatsforsch Immunobiol. 1976 Nov;152(3):231–243. [PubMed] [Google Scholar]
  8. Dierich M. P., Hadding U., König W., Limbert M., Schorlemmer H. U., Bitter-Suermann D. Factor D in the alternate pathway of complement activation: purification, physicochemical characterization and functional role. Immunochemistry. 1974 Sep;11(9):527–532. doi: 10.1016/0019-2791(74)90242-0. [DOI] [PubMed] [Google Scholar]
  9. Fearon D. T., Austen K. F. Properdin: initiation of alternative complement pathway. Proc Natl Acad Sci U S A. 1975 Aug;72(8):3220–3224. doi: 10.1073/pnas.72.8.3220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fearon D. T., Austen K. F., Ruddy S. Properdin factor D. II. Activation to D by properdin. J Exp Med. 1974 Aug 1;140(2):426–436. doi: 10.1084/jem.140.2.426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fearon D. T., Austen K. F., Ruddy S. Properdin factor D: characterization of its active site and isolation of the precursor form. J Exp Med. 1974 Feb 1;139(2):355–366. doi: 10.1084/jem.139.2.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fearon D. T. Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci U S A. 1978 Apr;75(4):1971–1975. doi: 10.1073/pnas.75.4.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Götze O., Müller-Eberhard H. J. The C3-activator system: an alternate pathway of complement activation. J Exp Med. 1971 Sep 1;134(3 Pt 2):90s–108s. [PubMed] [Google Scholar]
  14. Götze O., Müller-Eberhard H. J. The role of properdin in the alternate pathway of complement activation. J Exp Med. 1974 Jan 1;139(1):44–57. doi: 10.1084/jem.139.1.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hunsicker L. G., Ruddy S., Austen K. F. Alternate complement pathway: factors involved in cobra venom factor (CoVF) activation of the third component of complement (C3). J Immunol. 1973 Jan;110(1):128–138. [PubMed] [Google Scholar]
  16. March S. C., Parikh I., Cuatrecasas P. A simplified method for cyanogen bromide activation of agarose for affinity chromatography. Anal Biochem. 1974 Jul;60(1):149–152. doi: 10.1016/0003-2697(74)90139-0. [DOI] [PubMed] [Google Scholar]
  17. McConahey P. J., Dixon F. J. A method of trace iodination of proteins for immunologic studies. Int Arch Allergy Appl Immunol. 1966;29(2):185–189. doi: 10.1159/000229699. [DOI] [PubMed] [Google Scholar]
  18. Medicus R. G., Götze O., Müller-Eberhard H. J. Alternative pathway of complement: recruitment of precursor properdin by the labile C3/C5 convertase and the potentiation of the pathway. J Exp Med. 1976 Oct 1;144(4):1076–1093. doi: 10.1084/jem.144.4.1076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Müller-Eberhard H. J., Götze O. C3 proactivator convertase and its mode of action. J Exp Med. 1972 Apr 1;135(4):1003–1008. doi: 10.1084/jem.135.4.1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. NILSSON U. R., MUELLER-EBERHARD H. J. ISOLATION OF BETA IF-GLOBULIN FROM HUMAN SERUM AND ITS CHARACTERIZATION AS THE FIFTH COMPONENT OF COMPLEMENT. J Exp Med. 1965 Aug 1;122:277–298. doi: 10.1084/jem.122.2.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pangburn M. K., Müller-Eberhard H. J. Complement C3 convertase: cell surface restriction of beta1H control and generation of restriction on neuraminidase-treated cells. Proc Natl Acad Sci U S A. 1978 May;75(5):2416–2420. doi: 10.1073/pnas.75.5.2416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. ROBBINS K. C., SUMMARIA L., ELWYN D., BARLOW G. H. FURTHER STUDIES ON THE PURIFICATION AND CHARACTERIZATION OF HUMAN PLASMINOGEN AND PLASMIN. J Biol Chem. 1965 Jan;240:541–550. [PubMed] [Google Scholar]
  23. ROBERTS P. S. Measurement of the rate of plasmin action on synthetic substrates. J Biol Chem. 1958 May;232(1):285–291. [PubMed] [Google Scholar]
  24. Reisfeld R. A., Pellegrino M. A., Ferrone S. The immunologic and molecular profiles of HLA antigens isolated from urine. J Immunol. 1977 Jan;118(1):264–269. [PubMed] [Google Scholar]
  25. Robbins K. C., Summaria L. Plasminogen and plasmin. Methods Enzymol. 1976;45:257–273. doi: 10.1016/s0076-6879(76)45025-5. [DOI] [PubMed] [Google Scholar]
  26. Schreiber R. D., Götze O., Müller-Eberhard H. J. Alternative pathway of complement: demonstration and characterization of initiating factor and its properdin-independent function. J Exp Med. 1976 Oct 1;144(4):1062–1075. doi: 10.1084/jem.144.4.1062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schreiber R. D., Götze O., Müller-Eberhard H. J. Nephritic factor: its structure and function and its relationship to initiating factor of the alternative pathway. Scand J Immunol. 1976;5(6-7):705–713. doi: 10.1111/j.1365-3083.1976.tb03020.x. [DOI] [PubMed] [Google Scholar]
  28. Schreiber R. D., Medicus R. G., Gïtze O., Müller-Eberhard H. J. Properdin- and nephritic factor-dependent C3 convertases: requirement of native C3 for enzyme formation and the function of bound C3b as properdin receptor. J Exp Med. 1975 Sep 1;142(3):760–772. doi: 10.1084/jem.142.3.760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schreiber R. D., Pangburn M. K., Lesavre P. H., Müller-Eberhard H. J. Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3948–3952. doi: 10.1073/pnas.75.8.3948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sherry S., Alkjaersig N., Fletcher A. P. Comparative activity of thrombin on substituted arginine and lysine esters. Am J Physiol. 1965 Sep;209(3):577–583. doi: 10.1152/ajplegacy.1965.209.3.577. [DOI] [PubMed] [Google Scholar]
  31. Vogt W., Dames W., Schmidt G., Dieminger L. Complement activation by the properdin system: formation of a stoichiometric. C3 cleaving complex of properdin factor B with C36. Immunochemistry. 1977 Mar;14(3):201–205. doi: 10.1016/0019-2791(77)90195-1. [DOI] [PubMed] [Google Scholar]
  32. Vogt W., Schmidt G., Dieminger L., Lynen R. Formation and composition of the C3 activating enzyme complex of the properdin system. Sequential assembly of its components on solid-phase trypsin-agarose. Z Immunitatsforsch Exp Klin Immunol. 1975 Jul;149(5):440–455. [PubMed] [Google Scholar]
  33. Volanakis J. E., Schrohenloher R. E., Stroud R. M. Human factor D of the alternative complement pathway: purification and characterization. J Immunol. 1977 Jul;119(1):337–342. [PubMed] [Google Scholar]
  34. Weber K., Pringle J. R., Osborn M. Measurement of molecular weights by electrophoresis on SDS-acrylamide gel. Methods Enzymol. 1972;26:3–27. doi: 10.1016/s0076-6879(72)26003-7. [DOI] [PubMed] [Google Scholar]
  35. Yang C. C., Chang C. C., Hayashi K., Suzuki T., Ikeda K., Hamaguchi K. Optical rotatory dispersion and circular dichroism of cobrotoxin. Biochim Biophys Acta. 1968 Oct 21;168(2):373–376. doi: 10.1016/0005-2795(68)90164-5. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES