Evolution of the primate cathelicidin. Correlation between structural variations and antimicrobial activity.
Cathelicidin genes homologous to the human CAMP gene, coding for the host defense peptide LL-37, have been sequenced and analyzed in 20 primate species, including Great Apes, hylobatidae, cercopithecidae, callithricidae, and cebidae. The region corresponding to the putative mature antimicrobial peptide is subject to a strong selective pressure for variation, with evidence for positive selection throughout the phylogenetic tree relating the peptides, which favors alterations in the charge while little affecting overall hydrophobicity or amphipathicity. Selected peptides were chemically synthesized and characterized, and two distinct types of behavior were observed. Macaque and leaf-eating monkey RL-37 peptides, like other helical antimicrobial peptides found in insect, frog, and mammalian species, were unstructured in bulk solution and had a potent, salt and medium independent antimicrobial activity in vitro, which may be the principal function also in vivo. Human LL-37 and the orangutan, hylobates, and callithrix homologues instead showed a salt-dependent structuring and likely aggregation in bulk solution that affected antimicrobial activity and its medium dependence. The two types of peptides differ also in their interaction with host cells. The evolution of these peptides has thus resulted in distinct mechanisms of action that affect the direct antimicrobial activity and may also modulate accessory antimicrobial functions due to interactions with host cells.
Zelezetsky
Igor
I
Department of Biochemistry, University of Trieste, Trieste, I-34127, Italy.
Pontillo
Alessandra
A
Puzzi
Luca
L
Antcheva
Nikolinka
N
Segat
Ludovica
L
Pacor
Sabrina
S
Crovella
Sergio
S
Tossi
Alessandro
A
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics*; D002144:Callithrix / Q000235:genetics*; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D019143:Evolution, Molecular; D005091:Exons; D014644:Genetic Variation; D006801:Humans; D008322:Mammals; D008969:Molecular Sequence Data; D005810:Multigene Family; D016133:Polymerase Chain Reaction; D011148:Pongo pygmaeus / Q000235:genetics*; D016415:Sequence Alignment; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D017931:DNA Primers; D004247:DNA; D054804:Cathelicidins