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Structure and function of the anaphylatoxins

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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

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  1. Department of Immunology (IMM 18), Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, 92037, La Jolla, California, USA

    Tony E. Hugh

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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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