Biochemistry and biology of anaphylatoxins.
The molecular architecture of anaphylatoxins has been explored on several levels. Primary, secondary and tertiary structural parameters that dictate function of the C3a, C4a and C5a molecules are being elucidated with the aid of comparative sequence analyses, physical measurements and organic syntheses. Although C3a, C4a and C5a are biologically distinct mediators, as defined by their unique receptor systems, a common genetic origin is apparent from conserved features in their primary structures. Evidence is now available which suggests that similarities in the folding pattern of the anaphylatoxins may dictate a concensus conformation for each factor. We have learned from synthetic peptide studies that the binding (e.g. effector) site in anaphylatoxin molecules exists as a linear sequence contained in the C-terminal portion of the polypeptide. What is also evident is that a preferred conformation is defined for the binding site requiring a proper side chain orientation for optimal bioactivity. It is proposed that folding of the native structure stabilizes this conformation at the binding site. The binding site in C3a contains the essential residues LGLAR folded in an irregular or pseudo-beta-turn and stabilized by an adjacent alpha-helical segment. It is proposed that the alpha-helical segment influences orientation of the side chain residues in the 'binding site'. A similar model is evolving for C5a based on synthetic C5a peptides that express both spasmogenic and chemotactic activities. This helix turn model promises to be representative of an essential structural feature that determines anaphylatoxin activity. We believe that these models contribute significantly to our understanding of the molecular relationships between structure and function for these humoral mediators of inflammation.
D000595:Amino Acid Sequence; D000706:Anaphylatoxins / Q000032:analysis / Q000138:chemical synthesis / Q000502:physiology; D000818:Animals; D003176:Complement C3 / Q000032:analysis; D015926:Complement C3a; D003181:Complement C4 / Q000032:analysis; D015934:Complement C4a; D003182:Complement C5 / Q000032:analysis; D015936:Complement C5a; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008970:Molecular Weight; D009504:Neutrophils / Q000648:ultrastructure; D010455:Peptides / Q000032:analysis / Q000138:chemical synthesis / Q000502:physiology; D011487:Protein Conformation; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000032:analysis
D000706:Anaphylatoxins; D003176:Complement C3; D003181:Complement C4; D003182:Complement C5; D010455:Peptides; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015926:Complement C3a; D015934:Complement C4a; D015936:Complement C5a