Evolution of the Primate Cathelicidin

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.

[1]  Alessandro Tossi,et al.  Identification and optimization of an antimicrobial peptide from the ant venom toxin pilosulin. , 2005, Archives of biochemistry and biophysics.

[2]  Ziheng Yang,et al.  PAML: a program package for phylogenetic analysis by maximum likelihood , 1997, Comput. Appl. Biosci..

[3]  Domenico Romeo,et al.  Cathelicidins: a novel protein family with a common proregion and a variable C‐terminal antimicrobial domain , 1995, FEBS letters.

[4]  M. Wewers,et al.  A Novel P2X7 Receptor Activator, the Human Cathelicidin-Derived Peptide LL37, Induces IL-1β Processing and Release1 , 2004, The Journal of Immunology.

[5]  A. Amoroso,et al.  A study of host defence peptide β-defensin 3 in primates , 2003 .

[6]  J. Calafat,et al.  Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. , 2001, Blood.

[7]  M. Ståhle-Bäckdahl,et al.  The Human Cationic Antimicrobial Protein (hCAP18), a Peptide Antibiotic, Is Widely Expressed in Human Squamous Epithelia and Colocalizes with Interleukin-6 , 1999, Infection and Immunity.

[8]  A. Waring,et al.  RL-37, an Alpha-Helical Antimicrobial Peptide of the Rhesus Monkey , 2001, Antimicrobial Agents and Chemotherapy.

[9]  C. Groves.  Primates of the world: Distribution, abundance, and conservation , 1985, International Journal of Primatology.

[10]  Alessandro Tossi,et al.  Amphipathic, α‐helical antimicrobial peptides , 2000 .

[11]  M. Benincasa,et al.  Interaction of antimicrobial peptides with bacterial polysaccharides from lung pathogens , 2005, Peptides.

[12]  A. Tossi,et al.  Wide-spectrum antibiotic activity of synthetic, amphipathic peptides. , 1998, Biochemical and biophysical research communications.

[13]  James M. Wilson,et al.  Cathelicidins - a family of multifunctional antimicrobial peptides , 2003, Cellular and Molecular Life Sciences CMLS.

[14]  J. Johansson,et al.  Apolipoprotein A-I Binds and Inhibits the Human Antibacterial/Cytotoxic Peptide LL-37* , 1998, The Journal of Biological Chemistry.

[15]  R. Gennaro,et al.  Structural features and biological activities of the cathelicidin-derived antimicrobial peptides. , 2000, Biopolymers.

[16]  V. Nizet,et al.  Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. , 2003, The Journal of investigative dermatology.

[17]  Alan J. Waring,et al.  Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils , 1998, Antimicrobial Agents and Chemotherapy.

[18]  Y H Chen,et al.  Determination of the helix and beta form of proteins in aqueous solution by circular dichroism. , 1974, Biochemistry.

[19]  Alessandro Tossi,et al.  Controlled alteration of the shape and conformational stability of alpha-helical cell-lytic peptides: effect on mode of action and cell specificity. , 2005, The Biochemical journal.

[20]  M. Zanetti.  Cathelicidins, multifunctional peptides of the innate immunity , 2004, Journal of leukocyte biology.

[21]  Y. Shai,et al.  Mode of action of linear amphipathic α-helical antimicrobial peptides , 1998 .

[22]  A. Tossi,et al.  Design of synthetic antimicrobial peptides based on sequence analogy and amphipathicity. , 1997, European journal of biochemistry.

[23]  Y. Shai,et al.  Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. , 1999, Biochimica et biophysica acta.

[24]  R. Gallo,et al.  Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities , 2005, The Journal of Immunology.

[25]  Richard L. Gallo,et al.  Postsecretory Processing Generates Multiple Cathelicidins for Enhanced Topical Antimicrobial Defense1 , 2004, The Journal of Immunology.

[26]  P. Storici,et al.  An approach combining rapid cDNA amplification and chemical synthesis for the identification of novel, cathelicidin-derived, antimicrobial peptides. , 1997, Methods in molecular biology.

[27]  Y. Shai,et al.  Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. , 1999, The Biochemical journal.

[28]  J. Odeberg,et al.  The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. , 1996, European journal of biochemistry.

[29]  M. Boniotto,et al.  Effects of Positively Selected Sequence Variations in Human and Macaca fascicularis β-Defensins 2 on Antimicrobial Activity , 2004, Antimicrobial Agents and Chemotherapy.

[30]  Alessandro Tossi,et al.  Amphipathic α helical antimicrobial peptides. , 2001 .

[31]  Ji Ming Wang,et al.  Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells , 2000, The Journal of experimental medicine.

[32]  Z. Yang,et al.  Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. , 1998, Molecular biology and evolution.

[33]  N. Goldman,et al.  Codon-substitution models for heterogeneous selection pressure at amino acid sites. , 2000, Genetics.

[34]  J. Johansson,et al.  Antibacterial Activities of the Cathelicidins Prophenin (Residues 62 to 79) and LL-37 in the Presence of a Lung Surfactant Preparation , 2004, Antimicrobial Agents and Chemotherapy.

[35]  K. Berndt,et al.  Conformation-dependent Antibacterial Activity of the Naturally Occurring Human Peptide LL-37* , 1998, The Journal of Biological Chemistry.

[36]  R Higuchi,et al.  Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. , 2013, BioTechniques.

[37]  W. C. Osman Hill,et al.  Primates : comparative anatomy and taxonomy , 1953 .

[38]  C. Vogelmeier,et al.  Rhesus Monkey (Macaca mulatta) Mucosal Antimicrobial Peptides Are Close Homologues of Human Molecules , 2001, Clinical Diagnostic Laboratory Immunology.

[39]  David Eisenberg,et al.  The helical hydrophobic moment: a measure of the amphiphilicity of a helix , 1982, Nature.

[40]  M. Zanetti,et al.  The cathelicidins--structure, function and evolution. , 2005, Current protein & peptide science.