Summary
Chemical and physical characterization of the anaphylatoxin molecules have provided a reasonably clear description of the architecture of these bioactive proteins. The primary structures of C3a, C4a, and C5a from man and from a number of animal species have been elucidated, and it is apparent that the three anaphylatoxins are genetically related. The anaphylatoxin protein chains very in length from 74 to 78 residues and no fewer than 30% of the residues are homologous when comparing C3a, C4a, and C5a within or between species. Synthetic peptide studies have been instrumental in identifying molecular features essential for the function of anaphylatoxins. Information gleened from the structure-function studies with synthetic analogue peptides of the anaphylatoxins define putative “active sites” in these effector molecules. Linear sequences at the carboxy-terminus of C3a and C4a fulfill all of the criteria of an “active site,“ in that synthetic peptides of an identical sequence can mimic the biologic actions of the natural factors. In the case of human C3a, a crystallographic analysis has been performed and a three dimensional structure was elucidated at the 3.2 Å level. The crystalline structure of C3a provides valuable new information regarding the alpha helical regions and identifies the arrangement of intra-chain disulfide linkages. Taken together, the structural data now accumulated for anaphylatoxins permit molecular modelling of these proteins, designates favored conformational arrangements of the native structures, and specifically localizes the effector sites. Furthermore, elements at the essential active site have been defined with such precision that models are proposed detailing the exact nature of ligand interactions between anaphylatoxins and specific cellular receptors.
Biologic characterization of the anaphylatoxins continues at a rapid pace and each advance provides a clearer view of the role of these humoral mediators in host defense. A variety of responses to anaphylatoxins are known to occur at the cellular level and are mediated in a hormone-like fashion. Diversity of action for these factors at the tissue level is readily explained by the numerous cell types stimulated by the anaphylatoxins. Cellular responses to the anaphylatoxins are perhaps the most easily defined and studied; however, tissue and systemic effects more accurately reflect the physiologic role of anaphylatoxins. Considerable progress has been made in understanding the mechanisms whereby anaphylatoxins mediate two major tissue effects, namely enhancement of vascular permeability and induction of smooth muscle contraction. A predominant role for bioactive lipids derived from arachidonate has been identified as a major component of these responses. Also, progress is being made in elucidating relationships between Immoral and cellular mediators in eliciting tissue responses to the anaphylatoxins. As these mechanisms are clarified, the significance of systemic effects and involvement of these humoral mediators in pathophysiologic conditions will ultimately be understood.
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Abbreviations
- SCPN :
-
The serum carboxypeptidase N is a zinc-containing exopeptidase specific for the cationic amino acids, lysine and arginine; the single letter code for amino acids is used according to recommendations of IUPAC-IUB International Commission on Biochemical Nomenclature
- SRS-A :
-
slow reacting substance of anaphylaxis is a term used to identify the leukotriene mixture of LTC4 LTD4 and LTE4
References
Bjork J, Arfors K-E, Dahlen S-E, Hedqvist P (1981) In: Venge P, Lindborn A (eds) The inflammatory process. Chapter 6. Almqvist & Wiksell International, Stockholm, Sweden, p 103
Bjork J, Hedqvist P, Arfors K-E (1982) Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes. Inflammation 6: 189
Bodammer G, Vogt W (1970) Increase in vascular permeability of guinea pig skin induced by anaphylatoxin. Naunyn-Schmiedebergs Arch Pharmacol 266: 255
Bokisch VA, Muller-Eberhard HJ (1970) Anaphylatoxin inactivator of human plasma; its isolation and characterization as a carboxypeptidase. J Clin Invest 49: 2427
Caporale LH, Tippett PS, Erickson BW, Hugh TE (1980) The active site of C3a anaphylatoxin. J Biol Chem 255: 10758
Chenoweth DE, Hugh TE (1978) Demonstration of specific C5a receptor on intact human polymorphonuclear leukocytes. Proc Natl Acad Sci USA 75: 3943
Chenoweth DE, Hugh TE (1980) Binding, internalization and degradation of human C5a by human neutrophils. Fed Proc 39: 1049
Chenoweth DE, Hugh TE (1980) Human C5a and C5a analogs as probes of the neutrophil C5a receptor. Mol Immunol 17: 151
Chenoweth DE, Erickson BW, Hugh TE (1979) Human C5a-related synthetic peptides as neutrophil chemotactic factors. Biochem Biophys Res Commun 86: 227
Chenoweth DE, Rowe JG, Hugh TE (1979) A modified method for chemotaxis under agrose. J Immunol Methods 25: 337
Chou PY, Fasman GD (1974) Prediction of protein conformation. Biochemistry 13: 222
Clancy RM, Dahinden CA, Hugh TE (1984) Arachidonate metabolism by human polymorphonuclear leukocytes stimulated by N-formyl peptide or C5a is independent of phospholipase activation. Proc Natl Acad Sci USA 80: 7200
Cochrane CG, Muller-Eberhard HJ (1968) The derivation of two distinct anaphylatoxin activities from the third and fifth components of human complement. J Exp Med 127: 371
Corbin NC, Hugh TE (1976) The primary structure of porcine C3a anaphylatoxin. J Immunol 117: 990
Craddock PR, Hammerschmidt D, White JG, Dalmasso AP, Jacob HS (1977) Complement (C5a)induced granulocyte aggregation in vitro: a possible mechanism of complement-mediated leukostasis and leukopenia. J Clin Invest 60: 260
Dahinden CA, Fehr J, Hugh TE (1983) Role of cell surface contact on the kinetics of superoxide production by granulocytes. J Clin Invest 72: 113
Damerau B, Zimmermann B, Wustefeld K, Czorniak K, Vogt W. (1983) Involvement of the N-terminus of hog C3a, C5a and C5ades Arg in their biological activities. Immunobiology 164: 229 (abstract)
Daniele RP (1981) Immune complex injury of the lung. Am J Resp 124: 735
Desai U, Kreutzer DL, Showell H, Arroyave CV, Ward PA (1979) Acute inflammatory pulmonary reactions induced by chemotactic factors. Am J Pathol 96: 71
Fernandez HN, Hugh TE (1976) Partial characterization of human C5a anaphylatoxin. I. Chemical description of the carbohydrate and polypeptide portions of human C5a. J Immunol 117: 1688
Fernandez HN, Hugh TE (1978) Primary structural analysis of the polypeptide portion of human C5a anaphylatoxin. I. Polypeptide sequence determination and assignment of the oligosaccharide attachment site in C5a. J Biol Chem 253: 6955
Fernandez HN, Henson PM, Hugli TE (1978) Chemotactic response to human C3a and C5a anaphylatoxins. I. Evaluations of C3a and C5a leukotaxis in vivo and in vitro. J Immunol 120: 109
Fey GH, Domdey H, Wiebauer K, Whitehead AS, Odink K (1983) Structure and expression of the C3 gene. Springer Seminars Immunopathol 6: 119
Fey GH, Wiebauer K, Domdey H (in press) Amino acid sequences of mouse complement C3 derived from nucleotide sequences of cloned cDNA. Ann NY Acad Sci
Friedberger E (1910) Weitere Untersuchungen über Eiweißanaphylaxie. IV. Mitteilung. Z Immunitätsforsch Exp Ther 4: 636
Gerard C, Hugh TE (1980) Amino acid sequence of the anaphylatoxin from the fifth component of porcine complement. J Biol Chem 255: 4710
Gerard C, Chenoweth DE, Hugh TE (1979) Molecular aspects of the serum chemotactic factors. J Reticuloendothel Soc 26: 711
Gerard C, Chenoweth DE, Hugh TE (1981) Response of human neutrophils to C5a: A role for the oligosaccharide moiety of human C5ades Arg-74 but not of C5a in biological activity. J Immunol 127: 1978
Glovsky MM, Hugh TE, Ishizaka T, Lichenstein LM, Erickson BW (1979) Anaphylatoxin-induced histamine release with human leukocytes: studies of C3a leukocyte binding and histamine release. J Clin Invest 64: 804
Goetzl EJ, Austen KF (1974) Stimulation of human neutrophil leukocyte aerobic glucose metabolism by purified chemotactic factors. J Clin Invest 53: 591
Goldstein IM, Feit F, Weissmann G (1975) Enhancement of nitroblue tetrazolium dye reduction by leukocytes exposed to a component of complement in the absence of phagocytosis. J Immunol 114: 516
Gorski JP, Hugh TE, Muller-Eberhard HJ (1981) Characterization of human C4a anaphylatoxins. J Biol Chem 256: 2707
Hammerschmidt DE, Harris P, Wayland JH, Jacob IS (1978) Intravascular granulocyte (PMN) aggregation in live animals: a complement (C) mediated mechanism of ischemia. Blood 52 [Suppl 1] 125
Hausman MS, Snyderman R, Mergenhagen SE (1972) Humoral mediators of chemotaxis of mononuclear leukocyte. J Infect Dis 125: 6
Havemann K, Janoff A (Eds) (1978) Neutral proteases of human polymorphonuclear leukocytes. Urban and Schwarzenberg, Baltimore
Henson PM, Zanolari B, Schwartzman NA, Hong SR (1978) Intracellular control of human neutrophil secretion. 1. C5a-induced stimulus-specific desensitization and the effects of cytochalasin B. J Immunol 121: 851
Henson PM, McCarthy K, Larsen GL, Webster RO, Giclas PC, Dreisen RB, King TE, Shaw JD (1979) Complement fragments, alveolar macrophages and alveolitis. Am J Pathol 97: 93
Hill JH, Ward PA (1969) C3 leukotactic factors produced by a tissue protease. J Exp Med 130: 505
Huber R, Scholze H, Paques EP, Deisenhofer J (1980) Crystal structure analysis and molecular model of human C3a anaphylatoxin. Hoppes-Seylers Z Physiol Chem 361: 1389
Huey R, Bloor CM, Kawahara MS, Hugli TE (1983) Potentiation of the anaphylatoxins in vivo using an inhibitor of serum carboxypeptidase N (SCPN). I. Lethality and effects on pulmonary tissue. Am J Pathol 112: 48
Hugh TE (1975) Human anaphylatoxin (C3a) from the third component of complement: Primary structure. J Biol Chem 250: 8293
Hugh TE (1981) The complement anaphylatoxins. In: Hofstaetter T, Schorlemmer HU (aeds) Topics in allergology. Vol 68. Behring Institute Mitteilungen, Die Medizinische Verlagsgesellschaft mbH, Marburg, p 68
Hugh TE (1981) The structural basis for anaphylatoxin in chemotactic functions of C3a and C5a. CRC Crit Rev Immunol I: 321–366
Hugh TE (1982) Bioactive factors of the blood complement system. In: Bradshaw RA, Hill RL, Tang J (eds) Proteins in biology and medicine. Proceedings of P.R.C.-USA Conference in Shanghai, China, Academic Press, New York, pp 91–117
Hugh TE (1983) Action of the anaphylatoxins on pulmonary tissues. In: Bostrom H, Youngsted N (eds) Theoretical and clinical aspects of allergic diseases, Scandia International Symposium (October 12–14, 1982). Almqvist & Wiksell International. Stockholm, pp 197–210
Hugli TE (1983) The chemistry and biology of C3a, C4a and C5a and their effect on cells. John Jacob Abel Symposium, Baltimore, Maryland, June 21–22, 1982. In: August JT (ed) Biological response mediators and modulators. Academic Press, New York, p 99
Hugh TE, Erickson BW (1977) Synthetic peptides with the biological activities and specificity of human C3a anaphylatoxin. Proc Natl Acad Sci USA 74: 1826
Hugh TE, Muller-Eberhard HJ (1978) Anaphylatoxins: C3a and C5a. Adv Immunol 26: 1–53
Hugli TE, Morgan WT, Muller-Eberhard HJ (1975) Circular dichroism of C3 a anaphylatoxin: effects of pH, heat, guanidinium chloride and mercaptoethanol on conformation and function. J Biol Chem 250:1479
Hugh TE, Kawahara MS, Unson CG, Molinor RL, Erickson BW (1983) The active site of human C4a anaphylatoxins. Mol Immunol 20: 637
Hugh TE, Stimler NP, Bloor CM (1983) Immunopharmacology of complement anaphylatoxins in the lung. In: Newhall HH (ed) Immunopharmacology of the lung, Vol. 19. Marcel Dekker, Inc, New York, pp 401–434
Issekutz AC, Movat KW, Movat HZ (1980) Enhanced vascular permeability and haemorrhage-inducing activity of rabbit C5adesArg: probable role of polymorphonuclear leucocyte lysosomes. Clin Exp Immunol 41: 512
Jacob HS, Craddock RB, Hammerschmidt DE, Moldow CF (1980) Complement-induced granulocyte aggregation. An unsuspected mechanism of disease. N Engl J Med 302: 789
Jacobs JW, Rubin JS, Hugh TE, Bogardt RA, Mariz IK, Daniels JS, Daughaday WH, Bradshaw RA (1978) Purification, characterization, and amino acid sequence of rat anaphylatoxin (C3a). Biochemistry 17: 5031
Janoff A, White R, Carp H, Harel S, Dearing R, Lee D (1979) Lung injury induced by leukocytic proteases. Am J Pathol 97: 111
Johnson AR, Hugli TE, Muller-Eberhard HJ (1975) Release of histamine from mast cells by the complement peptides C3a and C5a. Immunology 28: 1067
Jose PJ, Forrest MJ, Williams TJ (1981) Human C5adesArg increases vascular permeability. J Immunol 127: 2376
Kay AB (1970) Studies on eosinophil leucocyte migration. II. Factors specifically chemotactic for eosinophils and neutrophils generated from guinea pig serum by antigen-antibody complexes. Clin Exp Immunol 1: 723
Kay AB, Shin HS, Austin KF (1973) Selective attraction of eosinophils and synergism between eosinophil chemotactic factor of anaphylaxis (ECF-A) and a fragment cleaved from the fifth component of complement (C5a). Immunology 24: 969
Lepow IH, Willms-Kretschmer K, Patrick RA, Rosen FS (1970) Gross and ultrastructural observations of lesions produced by intradermal injection of human C3a in man. Am J Pathol 61: 13
Lett-Brown MA, Boetcher DA, Leonard EJ (1976) Chemotactic responses of normal human basophils to C5a and to lymphocyte-derived chemotactic factor. J Immunol 117: 246
Lu Z, Fok KF, Erickson BW, Hugh TE (in press) Conformational analysis of COOH-terminal fragments of human C3a: Evidence of ordered conformation in an active monocosapeptide. J Biol Chem
McCarthy K, Henson PM (1979) Induction of lysosomal enzyme secretion by alveolar macrophages in response to the purified fragments C5a and C5ades Arg. J Immunol 123: 2511
Moon KE, Gorski JP, Hugh TE (1981) Complete primary structure of human C4a anaphylatoxin. J Biol Chem 256: 8685
O'Flaherty JT, Ward PA (1979) Leukocyte aggregation induced by chemotactic factors. Inflammation 3: 177
O'Flaherty JT, Kreutzer DL, Ward PA (1978) Chemotactic factor influences on the aggregation, swelling, and foreign surface adhesiveness of human leukocytes. Am J Pathol 90: 537
Paques EP, Scholze H, Huber R (1980) Purification and crystallization of human anaphylatoxin C3a. Hoppe Seylers Z Physiol Chem 361: 915
Plummer HR Jr, Hurwitz NY (1978) Human plasma carboxypeptidase. J Biol Chem 253: 3907
Regal JF, Pickering RG (1979) The effect of C5a on the isolated guinea pig trachea. Fed Proc 38: 848
Regal JF, Eastman AY, Pickering RJ (1980) C5a-induced tracheal contraction: a histamine independent mechanism. J Immunol 124: 2876
Schiffman E, Corcoran BA, Wahl SM (1975) N-Formylmethionyl peptides as chemattractants for leukocytes. Proc Natl Acad Sci USA 72: 1059
Shin HS, Snyderman R, Friedman E, Mellors A, Mayer MM (1968) Chemotactic and anaphylatoxic fragment cleaved from the fifth component of guinea pig complement. Science 162: 361
Smith MA, Gerrie LM, Dunbar B, Fothergill JE (1982) Primary structure of bovine complement activation fragment C4a, the third anaphylatoxin. Biochem J 207: 253
Snyderman R, Shin HS, Hausman MH (1971) A chemotactic factor for mononuclear leukocytes. Proc Soc Exp Biol Med 138: 387
Stimler NP, Brocklehurst WE, Bloor CM, Hugh TE (1980) Complement anaphylatoxin C5a stimulates release of SRS-A-like activity from guinea pig lung fragments. Letter to the Editor. J Pharm Pharmacol 32: 804
Stimler NP, Hugh TE, Bloor CM (1980) Pulmonary injury induced by C3a and C5a anaphylatoxins. Am J Pathol 100: 327
Stimler NP, Brocklehurst WE, Hugli TE, Bloor CM (1981) Anaphylatoxin-mediated contraction of guinea pig lung strips: a non-histamine tissue response. J Immunol 126: 2258
Stimler NP, Bach MK, Bloor CM, Hugh TE (1982) Release of leukotrienes from guinea pig lung stimulated by C5ades Arg anaphylatoxin. J Immunol 128: 2247
Stimler NP, Bloor CM, Hugli TE (1983) C3a-induced contraction of guinea pig lung parenchymal: role of cyclooxygenase metabolites. Immunopharmacology 5: 251
Unson CG, Erickson BW, Hugli TE (in press) Active site of C3a anaphylatoxin: contributions of the lipophilic and orienting residues. Biochemistry
Vallota EH, M üler-Eberhard HJ (1973) Formation of C3a and C5a anaphylatoxins in whole human serum after inhibition of the anaphylatoxin inactivator. J Exp Med 137: 1109
Vogt W (1974) Activation, activities and pharmacologically active products of complement. Pharmacol Rev 26: 125
Ward PA (1967) A plasmin-split fragment of C3 as a new chemotactic factor. J Exp Med 126: 189
Ward PA (1968) Chemotaxis of mononuclear cells. J Exp Med 128: 1201
Ward PA (1979) Immune complex injury of the lung. Am J Pathol 97: 85
Ward PA, Newman LJ (1969) A neutrophil chemotactic factor from human C5. J Immunol 120: 93
Weigle WO, Morgan EL, Goodman MG, Chenoweth DE, Hugh TE (1982) Modulation of the immune response by anaphylatoxin in the microenvironment of the interacting cell. Fed Proc 41: 3099
Weigle WO, Goodman MG, Morgan EL, Hugli TE (1983) Regulation of immune response by components of the complement cascade and their activated fragments. Springer Seminar Immunopathol 6: 173
Wissler JH (1972) Chemistry and biology of the anaphylatoxin related serum peptide system. I. Purification, crystallization and properties ofclassical anaphylatoxin from rat serum. Eur J Immunol 2: 73
Wuepper RB, Bokisch VA, Müller-Eberhard HJ, Stoughton RB (1972) Cutaneous responses to human C3 anaphylatoxin in man. Clin Exp Immunol 11: 13
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Hugh, T.E. Structure and function of the anaphylatoxins. Springer Semin Immunopathol 7, 193–219 (1984). https://doi.org/10.1007/BF01893020
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DOI: https://doi.org/10.1007/BF01893020