Structure of anaphylatoxins

The complement fragments C3a, C4a and C5a released during complement activation are, in humans, 77-74 amino acid residues in length, and share, as their parent proteins C3, C4 and C5, significant homology in their primary sequence. They all have a core with three disulfide bridges. More importantly, crystallographic data of C3a and nuclear magnetic resonance (NMR) studies of C3a and C5a in solution showed that C3a and C5a have very similar secondary and tertiary structures. The first 63 residues of C5a in solution form an antiparal-lel bundle of four helices similar to the coiled-coil arrangement of helices in many other four-helix proteins, while the C-terminus is disordered. The helices I, II, and IV are quite regular and are compatible with an a-helical pitch. The N-terminal helix is amphiphilic and its hydrophobic residues are inter-digitated with hydrophobic residues on helices 11 and IV. The structure of C5a seems to differ somewhat from the crystal structure of C3a, which shows a disordered N-terminus and a helical C-terminus, but NMR investigations of C3a in solution indicate that the terminal regions of both anaphylatoxins are similar.

Thus, based on similarities of bioactivity, of their receptors as well as of their structure, the anaphylatoxins must be regarded as a family of closely related molecules. Anaphylatoxins of other species are most likely very similar in structure as well. Furthermore, the bioactivity of C3a and C5a is not species restricted, as is the case for many cytokines. Human C5a has, however, some notable peculiarities. First, there is a N-terminal odd cysteine at position 27 in the loop connecting helix II with helix III, facing towards the solvent. It can be attached to molecules such as glutathione without effect on bioactivity, and it may covalently link to other proteins with a free accessible -SH group under an oxidative environment. Indeed, yet poorly defined high molecular weight chemotactic factors have been described in scrum. Second, a bulky sugar moiety is attached in human C5a near the C-terminus which is of major importance in receptor activation. This glycosylation may be responsible in part for the fact that natural human C5adesarB is a potent chemoattractant but a ver\ ineffective cell activator and spasmogen.

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