Primate beta-defensins--structure, function and evolution (original) (raw)
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Primate β-defensins - Structure, Function and Evolution
Current Protein & Peptide Science, 2005
Host defense peptides (HDPs) are endogenous antibiotics that play a multifunctional role in the innate immunity of mammals. Among these, β-defensins contribute to mucosal and epithelial defense, also acting as signal molecules for cellular components of innate and adaptive immunity. Numerous members of this family have been identified in mammalian and avian species, and genomic studies in human and mouse indicate a considerable complexity in their gene organization. Recent reports on the evolution of primate and rodent members of this family indicate quite a complex pattern of variation. In this review we briefly discuss the evolution of mammalian β-defensins in relation to other types of defensins, and then concentrate on the evolution of β-defensins 1 to 4 in primates. In particular, the surprisingly varied patterns of evolution, which range from neutral or weakly purifying, to positive selection to a high level of conservation are analyzed in terms of possible genetics, structural or functional implications, as well as to observed variations on the antimicrobial activity in vitro. The role of polymorphisms in the genes encoding for these host defense peptides in determining susceptibility to human diseases are also briefly considered.
Primate β-defensins - Structure, Function and Evolution
Current Protein & Peptide Science, 2005
Host defense peptides (HDPs) are endogenous antibiotics that play a multifunctional role in the innate immunity of mammals. Among these, β-defensins contribute to mucosal and epithelial defense, also acting as signal molecules for cellular components of innate and adaptive immunity. Numerous members of this family have been identified in mammalian and avian species, and genomic studies in human and mouse indicate a considerable complexity in their gene organization. Recent reports on the evolution of primate and rodent members of this family indicate quite a complex pattern of variation. In this review we briefly discuss the evolution of mammalian β-defensins in relation to other types of defensins, and then concentrate on the evolution of β-defensins 1 to 4 in primates. In particular, the surprisingly varied patterns of evolution, which range from neutral or weakly purifying, to positive selection to a high level of conservation are analyzed in terms of possible genetics, structural or functional implications, as well as to observed variations on the antimicrobial activity in vitro. The role of polymorphisms in the genes encoding for these host defense peptides in determining susceptibility to human diseases are also briefly considered.
Evolution of the beta defensin 2 gene in primates
Genes and Immunity, 2003
With the aim of further investigating the molecular evolution of beta defensin genes, after having analysed beta defensin 1 (DEFB1) in humans and several nonhuman primate species, we have studied the evolution of the beta defensin 2 gene (DEFB2), which codifies for a peptide with antimicrobial and chemoattractant activity, in humans and 16 primate species. We have found evidence of positive selection during the evolution of orthologous DEFB2 genes at two points on a phylogenetic tree relating these primates: during the divergence of the platyrrhines from the catarrhines and during the divergence of the Cercopithecidae from the Hylobatidae, Great Apes and humans. Furthermore, amino acid variations in Old World Monkeys seem to centre either on residues that are involved in oligomerisation in the human molecule, or that are conserved (40-80%) in beta-defensins in general. It is thus likely that these variations affect the biological function of the molecules and suggest that their synthesis and functional analysis might reveal interesting new information as to their role in innate immunity.
A study of host defence peptide β-defensin 3 in primates
Biochemical Journal, 2003
We have investigated the molecular evolution of the gene coding for β-defensin 3 (DEFB103) in 17 primate species including humans. Unlike the DEFB4 genes (coding for β-defensin 2) Genes Immun. 4, 251-257], DEFB103 shows a marked degree of conservation in humans, Great Apes and New and Old World monkeys. Only the Hylobates concolor defensin hcBD3 showed an amino acid variation Arg 17 →Trp 17 that could have a functional implication, as it disrupts an intramolecular salt bridge with Glu 27 , which locally decreases the charge and may favour dimerization in the human congener hBD3. This is thought to involve the formation of an intermolecular salt bridge between Glu 28 and Lys 32 on another monomer [Schibli, Hunter, Aseyev, Starner, Wiencek, McCray, Tack and Vogel (2002) J. Biol. Chem. [8279][8280][8281][8282][8283][8284][8285][8286][8287][8288][8289]. To test the role of dimerization in mediating biological activity, we synthesized hBD3, hcBD3 and an artificial peptide in which the Lys 26 -Glu 27 -Glu 28 stretch was replaced by the equivalent Phe-Thr-Lys stretch from human β-defensin 1 and we characterized their structure and anti-microbial activity. Although the structuring and dimerization of these peptides were found to differ significantly, this did not appear to affect markedly the anti-microbial potency, the broad spectrum of activity or the insensitivity of the anti-microbial action to the salinity of the medium.
Evolution of primate α and θ defensins revealed by analysis of genomes
Molecular Biology Reports, 2014
Defensins are endogenous peptides with cysteine-rich antimicrobial ability that contribute to host defence against bacterial, fungal and viral infections. There are three subfamilies of defensins in primates: a, b and hdefensins. a-defensins are most present in neutrophils and Paneth cells; b-defensins are involved in protecting the skin and the mucous membranes of the respiratory, genitourinary and gastrointestinal tracts; and h-defensins are physically distinguished as the only known fully-cyclic peptides of animal origin, which are first isolated from rhesus macaques. All three kinds of defensins have six conserved cysteines, three intramolecular disulfide bonds, a net positive charge, and b-sheet regions. a and h-defensins are closely related, comparative amino acid sequences showed that the difference between them is that h-defensins have an additional stop codon limits the initial defensin domain peptides to 12 residues. Humans, chimpanzees and gorillas do not produce h-defensin peptides due to a premature stop codon present in the signal sequence of all h-defensin pseudogenes. By using comprehensive computational searches, here we report the discovery of complete repertoires of the a and hdefensin gene family in ten primate species. Consistent with previous studies, our phylogenetic analyses showed all primate h-defensins evident formed one distinct clusters evolved from a-defensins. b-defensins are ancestors of both a and h-defensins. Human has two copies of DEFA1 and DEFT1P, and two extra DEFA3 and DEFA10P genes compared with gorilla. As different primates inhabit in quite different ecological niches, the production of species-specific a and h-defensins and these highly evolved h-defensins in old world monkeys would presumably allow them to better respond to the specific microbial challenges that they face. have contributed equally to this work.
Duplication and selection in the evolution of primate beta-defensin genes
Genome biology, 2003
Innate immunity is the first line of defense against microorganisms in vertebrates and acts by providing an initial barrier to microorganisms and triggering adaptive immune responses. Peptides such as beta-defensins are an important component of this defense, providing a broad spectrum of antimicrobial activity against bacteria, fungi, mycobacteria and several enveloped viruses. Beta-defensins are small cationic peptides that vary in their expression patterns and spectrum of pathogen specificity. Disruptions in beta-defensin function have been implicated in human diseases, including cystic fibrosis, and a fuller understanding of the variety, function and evolution of human beta-defensins might form the basis for novel therapies. Here we use a combination of laboratory and computational techniques to characterize the main human beta-defensin locus on chromosome 8p22-p23. In addition to known genes in the region we report the genomic structures and expression patterns of four novel hu...
Molecular Evolutionary Analysis of a-Defensin Peptides in Vertebrates
Rajshahi University Journal of Science and Engineering, 2016
α-Defensin is a group of polypeptides with antimicrobial activity found in the host defense system and it is widely distributed in, but not limited to mammalian epithelial cells and phagocytes. These molecules protect the organism from a diverse spectrum of bacteria, viruses, fungi, and protozoan parasites. Different studies have revealed widesequence variation within α-defensin sequences, but the underlying evolutionary cause is not well-studied. In this study, the α-defensin gene from 25 vertebrate species has been comprehensively collected and computationally analyzed. NCBI gene and nucleotide databases were accessed to extract meta-information about α-defensin gene's defensin domain and leader propeptide sequences. Full coding sequences downloaded from nucleotide database by splitting out intron sequence. MEGA software used to construct phylogenetic tree using Neighbor-Joining method, which indicates that α-defensin gene evolution does not matches with species evolution. Sel...
Evolution and Diversity of Defensins in Vertebrates
2017
Defensins are a large family of genes that were first characterised as encoding antimicrobial peptides, with a broad range of activity against viruses, bacteria and fungi. It is clear, however, that at least in vertebrates, they have acquired a variety of other roles in addition to direct antimicrobial activity, including cell signalling, reproduction and mammalian coat colour. In this article, we review the evolutionary history of the three types of defensins found in vertebrates, namely α-, β- and θ-defensins. We consider evolution at a deep timescale, where a pattern of duplication and divergence emerges, consistent with birth-and-death evolution. At a more recent timescale, we consider the evolutionary genetics of defensins within species, particularly copy number variation which is observed for many defensins across several lineages. The different functions of at least some defensins in different evolutionary lineages raise some problems in inferring function based on identific...
Infection and Immunity
beta-Defensins are cationic peptides with broad-spectrum antimicrobial activity that may play a role in mucosal defenses of several organs. They have been isolated in several species, and in humans, two beta-defensins have been identified. Here, we report the identification of two genes encoding beta-defensin homologues in the rat. Partial cDNAs were found by searching the expressed-sequence-tag database, and primers were designed to generate full-length mRNA coding sequences. One gene was highly similar to the human beta-defensin-1 (HBD-1) gene and mouse beta-defensin-1 gene at both the nucleic acid and amino acid levels and was termed rat beta-defensin-1 (RBD-1). The other gene, named RBD-2, was homologous to the HBD-2 and bovine tracheal antimicrobial peptide (TAP) genes. The predicted prepropeptides were strongly cationic, were 69 and 63 residues in length for RBD-1 and RBD-2, respectively, and contained the six-cysteine motif characteristic of beta-defensins. The beta-defensin ...