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J. Biol. Chem., Vol. 281, Issue 29, 19861-19871, July 21, 2006

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Evolution of the Primate Cathelicidin

CORRELATION BETWEEN STRUCTURAL VARIATIONS AND ANTIMICROBIAL ACTIVITY^*

Igor Zelezetsky¹², Alessandra Pontillo¹, Luca Puzzi, Nikolinka Antcheva, Ludovica Segat, Sabrina Pacor^¶, Sergio Crovella, and Alessandro Tossi³

From the Departments of Biochemistry, Biophysics and Macromolecular Chemistry, Reproduction and Development Sciences, and ^¶Biomedical Sciences, University of Trieste, Trieste, I-34127 Italy

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.

Received for publication, October 12, 2005 , and in revised form, May 23, 2006.

^* This work was supported in part by grants from the Italian Ministry of Universities and Scientific Research (PRIN 2003) and a Friuli-Venezia Giulia regional grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

The nucleotide sequence(s) reported in this paper has been submitted to the Gen-Bank^TM/EBI Data Bank with accession number(s) CAMP_afr DQ471354 [GenBank] ; CAMP_afu DQ471355 [GenBank] ; CAMP_cae DQ471356 [GenBank] ; CAMP_cca DQ471357 [GenBank] ; CAMP_cja DQ471358 [GenBank] ;CAMP_ggoDQ471359; CAMP_hcgDQ471360; CAMP_hclDQ471361; CAMP_hco DQ471362 [GenBank] ; CAMP_hle DQ471363 [GenBank] ; CAMP_hmd DQ471364 [GenBank] ; CAMP_mfa DQ471365 [GenBank] ; CAMP_mto DQ471366 [GenBank] ; CAMP_pcr DQ471367 [GenBank] ; CAMP_pob DQ471368 [GenBank] ; CAMP_ppa DQ471369 [GenBank] ; CAMP_ppy DQ471370 [GenBank] ; CAMP_ptr DQ471371 [GenBank] ; CAMP_soe DQ471372 [GenBank] .

¹ Both authors contributed equally to this work.

² Supported by fellowships from the Consortium for International Development of the University of Trieste and the Central European Initiative.

³ To whom correspondence should be addressed. Tel.: 39-040-5583673; Fax: 39-040-5583691; E-mail: tossi{at}bbcm.units.it.

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