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Selective Reciprocity in Antimicrobial Activity Versus Cytotoxicity of Hbd-2 and Crotamine

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Selective Reciprocity in Antimicrobial Activity Versus Cytotoxicity of Hbd-2 and Crotamine Selective reciprocity in antimicrobial activity versus cytotoxicity of hBD-2 and crotamine Nannette Y. Younta,b, Deborah Kupferwassera,b, Alberto Spisnic, Stephen M. Dutzd, Zachary H. Ramjand, Shantanu Sharmad, Alan J. Waringe, and Michael R. Yeamana,b,e,1 aDivision of Infectious Diseases, LAC-Harbor University of California, Los Angeles Medical Center, Torrance, CA 90509; bSt. John’s Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor–University of California, Los Angeles, Torrance, CA 90502; cDepartment of Experimental Medicine, Section of Chemistry and Structural Biology, University of Parma, 43100 Parma, Italy; dDepartment of Chemistry and Center for Macromolecular Modeling and Materials Design, California State Polytechnic University, Pomona, CA 91768; and eDepartment of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90024 Edited by H. Ronald Kaback, University of California, Los Angeles, CA, and approved June 24, 2009 (received for review April 23, 2009) Recent discoveries suggest cysteine-stabilized toxins and antimi- fensin and crotamine-like toxin families, but conserved cysteine- crobial peptides have structure–activity parallels derived by com- array and ␥-core motifs (4). In the present study, evolutionary, mon ancestry. Here, human antimicrobial peptide hBD-2 and rat- structural, and mechanistic investigations were performed to ad- tlesnake venom-toxin crotamine were compared in phylogeny, 3D dress the hypothesis that reciprocal relationships exist between structure, target cell specificity, and mechanisms of action. Results antimicrobial and cytotoxic host defense peptides. indicate a striking degree of structural and phylogenetic congru- ence. Importantly, these polypeptides also exhibited functional Results reciprocity: (i) they exerted highly similar antimicrobial pH optima Phylogenetic, structural, mechanistic, and target interaction and spectra; (ii) both altered membrane potential consistent with comparisons between hBD-2 and crotamine were investigated ion channel-perturbing activities; and (iii) both peptides induced through complementary methods. phosphatidylserine accessibility in eukaryotic cells. However, the Nav channel-inhibitor tetrodotoxin antagonized hBD-2 mecha- Phylogenetic Analysis. Crotamine and related serpentine toxins nisms, but not those of crotamine. As crotamine targets eukaryotic formed a monophyletic group with robust statistical confidence IMMUNOLOGY ion channels, computational docking was used to compare hBD-2 (Fig. 1). A single subclade in this group was represented by crotasin, versus crotamine interactions with prototypic bacterial, fungal, or a ␤-defensin from the nonvenomous somatic tissues of Crotalus mammalian Kv channels. Models support direct interactions of each durissus terrificus (7). A sister group was comprised of 2 crotamine- peptide with Kv channels. However, while crotamine localized to like proteins (CLP) from the venom of the bearded dragon Pogona occlude Kv channels in eukaryotic but not prokaryotic cells, hBD-2 barbata (6). The next most closely related sequences are ␤-defensins interacted with prokaryotic and eukaryotic Kv channels but did not from various avian species. Notably, the serpentine and avian occlude either. Together, these results support the hypothesis that sequences form a unified clade within the Sauropsida. These antimicrobial and cytotoxic polypeptides have ancestral structure- findings suggest a divergence of peptides optimized for antimicro- function homology, but evolved to preferentially target respective bial versus cytotoxic functions appeared concomitant with the microbial versus mammalian ion channels via residue-specific in- divergence of synapsids (mammals) from sauropsids (aves/reptiles) teractions. These insights may accelerate development of anti- (SI Text and Figs. S1 and S2). infective or therapeutic peptides that selectively target microbial or abnormal host cells. Structural and Biophysical Comparison. Three-dimensional (3D) alignment between hBD-2 and crotamine revealed a striking degree ͉ ͉ ͉ channel defensin host defense toxin of identity (Fig. 2A). The greatest degree of 3D alignment (RMSD Յ2) occurs between respective ␣-helical and ␥-core regions. Thus, ysteine-stabilized antimicrobial polypeptides are thought to evolutionary selective pressures have favored conservation of 3D Cfunction as a first line of host defense. One of the most structure in the face of limited sequence identities (28%) of the 2 well-characterized groups of such molecules is the ␤-defensins peptides (2). Despite striking conformational homology, biophys- from myeloid and epithelial tissues of mammalian and avian ical analyses revealed significant physicochemical differences be- species. The ␤-defensins contain a highly conserved cysteine- tween hBD-2 and crotamine that likely relate to differences in array that affords structural rigidity and promotes hypervari- target preference. For example, the solvent accessible surface area ability for accelerated evolutionary adaptation. of hBD-2 (Ϸ70% lacking charged residues; Fig. 2B) is markedly Several parallels suggest structural, functional, and evolutionary more hydrophobic than that of crotamine. commonalities between defensins and other host defense and/or offense molecules, such as toxins. Like antimicrobial peptides, many Antimicrobial Activity. Crotamine antimicrobial activities paralleled toxins are small, cysteine-stabilized, and cationic (1, 2), and share those of hBD-2 at both experimental pH values against most a striking degree of conservation with host defense peptides that contain a ␥-core motif (3). One group of toxins with particularly close homology to ␤-defensins is the crotamine-myotoxin family Author contributions: N.Y.Y. and M.R.Y. designed research; N.Y.Y., D.K., S.M.D., Z.H.R., S.S., from South American rattlesnakes (4, 5). As in ␤-defensins, toxin A.J.W., and M.R.Y. performed research; N.Y.Y., A.S., S.S., and M.R.Y. contributed new expression is often targeted for mucosal or extracorporeal secretion reagents/analytic tools; N.Y.Y., S.M.D., Z.H.R., S.S., A.J.W., and M.R.Y. analyzed data; and N.Y.Y., A.S., S.S., A.J.W., and M.R.Y. wrote the paper. (6). Such toxins typically induce rapid paralysis resulting in local Conflict of interest statement: M.R.Y. is a shareholder of NovaDigm Therapeutics, Inc., and myonecrosis in skeletal muscle. Crotamine-like toxins are thought has received research funding from Pfizer, Inc., Amgen, Inc., Cubist Pharmaceuticals, and to induce such effects through targeting of ion channels and altering Novozymes Pharmaceuticals. None of these entities provided support for the current membrane transport or conductivity (5). studies. Understanding structural and mechanistic reciprocity is of direct This article is a PNAS Direct Submission. relevance to immunologic roles and potential therapeutic develop- 1To whom correspondence should be addressed. E-mail: [email protected]. ment of antimicrobial and cytotoxic peptide-based therapies. Prior This article contains supporting information online at www.pnas.org/cgi/content/full/ studies have noted overall diversity in primary structures of ␤-de- 0904465106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0904465106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 26, 2021 BNBD12_BOSTA BNBD8_BOSTA A HBD-2 CRO BNBD3_BOSTA TAP_BOSTA LAP_BOSTA BD402_BOSTA Artiodactyl SBD2_OVIAR SBD1_OVIAR β-defensins Synapsida BD1_CAPHI BD2_CAPHI EBD_BOSTA NBD4_BUBBU BNBD5_BOSTA BNBD4_BOSTA MBD8_MUSMU RBD3_RATNO Rodent RBD5_RATNO β-defensins MBD4_MUSMU BD2_MACMU Primate BD2_PANTR β-defensins BD2_HOMSA BD1_SUSSC BD1_EQUCA Mammalian BD1_CHILA β-defensins BD103_CANFA BD3_SUSSC BD7_GALGA BD_ANAPL BD2_GALGA GAL2_GALGA Avian BD5_GALGA β-defensins GAL9_GALGA Sauropsida GAL1_GALGA THP1_MELGA CLPPOGL2_POGBA Reptilian CLPPOGL3_POGBA Toxins CROTASIN_CRODU MYO3_CRODU CROT1_CRODU CROT3_CRODU MYO_CRODU Serpentine MYOA_CROVIV Toxins MYO2_CROVIC MYO3_CROVIV HBD-2 Crotamine MYO1_CROVIC B BD4_GALGA Avian GAL12_GALGA A BD8_GALGA β-defensins B Fig. 1. Phylogenetic parallels between crotamine and hBD-2. Neighbor-joining tree visualization (36) of the hBD-2/crotamine polypeptide family. Branch signif- icance was validated by bootstrap analysis. 180o C organisms (P Ͼ 0.05; Fig. 3). The only exception to this observation was for the prokaryote Staphylococcus aureus at pH 7.5, where hBD-2 had significantly greater efficacy (P Ͻ 0.05). Notably, both crotamine and hBD-2 had marked activity against the eukaryotic D pathogen Candida albicans at pH 7.5 or 5.5. Generally, hBD-2 had greater efficacy at pH 7.5, except against C. albicans, where pH had no discernable impact. E Cytotoxic Properties. To assess relative cytotoxicities of crotamine 90o versus hBD-2, flow cytometry was used to compare membrane electrophysiology (⌬⌿), permeabilization, and phosphatidylserine accessibility in bacteria and 2 eukaryotic cell systems. Fig. 2. Structure and biophysical comparison of crotamine and hBD-2. (A)3D Membrane Energetics. Membrane potential (⌬⌿) was evaluated alignment of crotamine/hBD-2 was performed by combinatorial extension (34). using 3,3-dipentyloxacarbocyanine (DiOC5), a charged lipophilic Coloration is per secondary structure schema: ␤-Sheet (blue); turn (gray); ␣-helix dye that emits a fluorescent signal proportional to ⌬⌿. The validity (red), molecular visualization MOLMOL (42). (B) Biophysical parallels in crotamine of this method to assess channel activity approaches the
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