The active site of human C4a anaphylatoxin

Area of Science:

• Immunology
• Biochemistry

Background:

• Human complement C4a peptide is biologically active and shares receptors with C3a anaphylatoxin.
• Both C3a and C4a induce smooth muscle contraction and cross-desensitization.

Purpose of the Study:

• To investigate the anaphylatoxic activities of synthetic C4a peptides.
• To identify the active site of C4a and compare its activity to C3a.

Main Methods:

• Synthesis of C4a pentapeptide, octapeptide, and analogs.
• Assay of peptide activity on isolated guinea-pig ileal strips.
• Assessment of wheal and flare reactions in skin.

Main Results:

• The C4a pentapeptide showed significantly lower activity than the C3a pentapeptide.
• Specific amino acid substitutions in the C4a pentapeptide enhanced its activity.
• The C4a octapeptide and its analogs demonstrated increased biological activity.
• Synthetic C4a peptides blocked C3a and C4a actions on smooth muscle.

Conclusions:

• The active site of C4a, similar to C3a, resides at its C-terminus.
• C4a may contribute to the kinin-like activity observed in hereditary angioneurotic edema (HANE).
• Reappraisal of the sole derivation of HANE edema from C2 or kininogens is suggested.