Primate cathelicidin orthologues display different structures and membrane interactions
Résumé
The human cathelicidin LL-37 displays both direct antibacterial activities and the capacity to modulate host cell activities. These depend on structural characteristics that are subject to positive selection for variation, as observed in a previous analysis of the CAMP gene in primates. The altered balance between cationic and anionic residues in different primate orthologues affects intramolecular salt-bridging and influences the stability of the peptides' helical conformation and tendency to aggregate in solution. We have analysed the effects of these structural variations on membrane interactions for human LL-37, rhesus RL-37, and orang-utan LL-37, using several complementary biophysical and biochemical methods. CD and ATR-FTIR spectroscopy on model membranes indicate that RL-37, which is monomeric and unstructured in bulk solution (F-form), and human LL-37, which is partly structured and likely aggregated (A-form), bind biological membranes in different manners. RL-37 may insert more deeply into the lipid bilayer than LL-37, which remains aggregated. AFM performed on the same supported bilayer as used for ATR-FTIR measurements suggests a carpet-like mode of permeabilization for RL37 and formation of more defined worm-holes for LL-37. Comparison of data from biological activity on bacterial cells with permeabilization of model membranes indicates that the structure/aggregation state also affects the trajectory of the peptides from bulk solution through the outer cell-wall layers to the membrane. Our data suggests that F-Form cathelicidin orthologues may have evolved to have primarily a direct antimicrobial defensive capacity while A-form ones have somewhat sacrificed this to gain host-cell modulating functions.
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