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1.C.19 The Defensin (Defensin) Family

Many organisms synthesize proteins (or peptides) which are degraded to relatively small hydrophobic or amphipathic, bioactive peptides. These peptides exhibit antibiotic, fungicidal, virucidal, hemolytic and/or tumoricidal activities by interacting with membranes and forming transmembrane channels that allow the free flow of electrolytes, metabolites and water across the phospholipid bilayers. Most of these peptides appear to function in biological warfare. There are many designations given to these bioactive peptides. They include the magainins, cecropins, melittins, defensins, bacteriocidins, etc. The proteins in each family within this functional superfamily are homologous, but they exhibit little or no significant sequence similarity with members of the other families. Thus, each family may have evolved independently. However, certain common structural features observed between members of distinct families suggest that at least some of these families share a common ancestry.

Several families of eukaryotic channel-forming amphipathic peptides, each from a different group of organisms, are recognized. These families will be listed below and briefly described.

Defensins are produced by mammals. Their precursors vary in size (35-95 amino acyl residues). The active peptides have antibacterial, antifungal and antiviral activities. The three-dimensional structures of defensin-1 have been solved both by x-ray crystallography (1.9 Å resolution) and by NMR. An α-defensin, HNP-1, a β-stranded toxin, forms a dimeric pore (Zhang et al., 2010).

Defensins contribute to innate immunity, including protection of mucosal tissues. Human α-defensin 6 (HD6) is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Chu et al. (2012) reported that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution (Chu et al., 2012).

The generalized transport reaction catalyzed by channel-forming amphipathic peptides is:

small solutes, electrolytes and water (in) small solutes, electrolytes and water (out).

 

This family belongs to the: Defensin Superfamily.

References associated with 1.C.19 family:

Bechinger, B. (1997). Structure and functions of channel-forming peptides: magainins, cecropins, melittin and alamethicin. J. Membr. Biol. 156: 197-211. 9096062
Bechinger, B., M. Zasloff and S.J. Opella (1993). Structure and orientation of the antibiotic peptide magainin in membrane by solid-state nuclear magnetic resonance spectroscopy. Prot. Sci. 2: 2077-2084. 8298457
Chu, H., M. Pazgier, G. Jung, S.P. Nuccio, P.A. Castillo, M.F. de Jong, M.G. Winter, S.E. Winter, J. Wehkamp, B. Shen, N.H. Salzman, M.A. Underwood, R.M. Tsolis, G.M. Young, W. Lu, R.I. Lehrer, A.J. Bäumler, and C.L. Bevins. (2012). Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337: 477-481. 22722251
Cummings, J.E. and T.K. Vanderlick. (2007). Kinetics of cryptdin-4 translocation coupled with peptide-induced vesicle leakage. Biochemistry. 46(42):11882-11891. 17910476
Ganz, T., J.R. Rayner, E.V. Valore, A. Tumolo, K. Talmadge and F. Fuller (1989). The structure of the rabbit macrophage defensin genes and their organ-specific expression. J. Immunol. 143: 1358-1365. 2745983
Gudmundsson, G.H., D.A. Lidholm, B. Asling, R.B. Gan and H.G. Boman (1991). The cecropin locus–cloning and expression of a gene cluster encoding 3 antibacterial peptides in Hyalophora cecropia. J. Biol. Chem. 266: 11510-11517. 1711035
Hill, C.P., J. Yee, M.E. Selsted and D. Eisenberg (1991). Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science 251: 1481-1485. 2006422
Kourie, J.I. and A.A. Shorthouse (2000). Properties of cytotoxic peptide-formed ion channels. Am. J. Physiol. Cell Physiol. 278: C1063-C1087. 10837335
Matsuzaki, K. (1998). Magainins as paradigm for the mode of action of pore forming polypeptides. Biochim. Biophys. Acta 1376: 391-400. 9804997
Nagaoka, I., A. Someya, K. Iwabuchi and T. Yamashita (1991). Characterization of cDNA clones encoding guinea pig neutrophil cationic peptides. FEBS Lett. 280: 287-291. 2013325
Pardi, A., X.L. Zhang, M.E. Selsted, J.J. Skalicky and P.F. Yip (1992). NMR studies of defensin antimicrobial peptides. 2. Three-dimensional structures of rabbit NP-2 and human HNP-1. Biochemistry 31: 11357-11364. 1445873
Terwilliger, T.C. and D. Eisenberg (1982). The structure of melittin. II. Interpretation of the structure. J. Biol. Chem. 257: 6016-6022.
Tran, D., P. Tran, K. Roberts, G. Osapay, J. Schaal, A. Ouellette, and M.E. Selsted. (2008). Microbicidal properties and cytocidal selectivity of rhesus macaque theta defensins. Antimicrob. Agents Chemother. 52(3): 944-953. 18160518
Vlasak, R., C. Unger-Ullmann, G. Kreil and A.M. Frischauf (1983). Nucleotide sequence of cloned cDNA coding for honeybee prepromelittin. Eur. J. Biochem. 135: 123-126. 6309516
Zhang, X.L., M.E. Selsted and A. Pardi (1992). NMR studies of defensin antimicrobial peptides. 1. Resonance assignment and secondary structure determination of rabbit NP-2 and human HNP-1. Biochemistry 31: 11348-11356. 1445872
Zhang, Y., W. Lu, and M. Hong. (2010). The membrane-bound structure and topology of a human α-defensin indicate a dimer pore mechanism for membrane disruption. Biochemistry 49: 9770-9782. 20961099