Dataset Information

Molecular Evolutionary Analysis of ?-Defensin Peptides in Vertebrates.

ABSTRACT: Vertebrate ?-defensins comprise an important family of antimicrobial peptides that protect organisms from a diverse spectrum of bacteria, viruses, fungi, and protozoan parasites. Previous studies have shown a marked variation in the number of ?-defensins among species, but the underlying reason is unclear. To address this question, we performed comprehensive computational searches to study the intact ?-defensin genes from 29 vertebrates. Phylogenetic analysis of the ?-defensin genes in vertebrates identified frequent changes in the number of ?-defensin genes and multiple species-specific gene gains and losses that have been occurring throughout the evolution of vertebrates. The number of intact ?-defensin genes varied from 1 in the western clawed frog to 20 in cattle, with numerous expansions and contractions of the gene family throughout vertebrates, especially among tetrapods. The ?-defensin gene number in a species is relevant to the ever-changing microbial challenges from the environment that they inhabit. Selection pressure analysis shows there exist three amino acid sites under significant positive selection. Protein structural characteristics analysis suggests that structural diversity determines the diverse functions of ?-defensins. Our study provides a new perspective on the relationships among vertebrate ?-defensin gene repertoires and different survival circumstances, which helps explain how ?-defensins have evolved.

SUBMITTER: Tu J

PROVIDER: S-EPMC4451809 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Molecular Evolutionary Analysis of β-Defensin Peptides in Vertebrates.

Tu Jianbo J Li Diyan D Li Qingqing Q Zhang Long L Zhu Qing Q Gaur Uma U Fan Xiaolan X Xu Huailiang H Yao Yongfang Y Zhao Xiaoling X Yang Mingyao M

Evolutionary bioinformatics online 20150601

Vertebrate β-defensins comprise an important family of antimicrobial peptides that protect organisms from a diverse spectrum of bacteria, viruses, fungi, and protozoan parasites. Previous studies have shown a marked variation in the number of β-defensins among species, but the underlying reason is unclear. To address this question, we performed comprehensive computational searches to study the intact β-defensin genes from 29 vertebrates. Phylogenetic analysis of the β-defensin genes in vertebrat ...[more]

PMID: 26056425

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Project description:The vertebrate genome is a result of two rapid and successive rounds of whole genome duplication, referred to as 1R and 2R. Furthermore, teleost fish have undergone a third whole genome duplication (3R) specific to their lineage, resulting in the retention of multiple gene paralogs. The more recent 3R event in teleosts provides a unique opportunity to gain insight into how genes evolve through specific evolutionary processes. In this study we compare molecular activities of vitamin D receptors (VDR) from basal species that diverged at key points in vertebrate evolution in order to infer derived and ancestral VDR functions of teleost paralogs. Species include the sea lamprey (Petromyzon marinus), a 1R jawless fish; the little skate (Leucoraja erinacea), a cartilaginous fish that diverged after the 2R event; and the Senegal bichir (Polypterus senegalus), a primitive 2R ray-finned fish. Saturation binding assays and gel mobility shift assays demonstrate high affinity ligand binding and classic DNA binding characteristics of VDR has been conserved across vertebrate evolution. Concentration response curves in transient transfection assays reveal EC50 values in the low nanomolar range, however maximum transactivational efficacy varies significantly between receptor orthologs. Protein-protein interactions were investigated using co-transfection, mammalian 2-hybrid assays, and mutations of coregulator activation domains. We then combined these results with our previous study of VDR paralogs from 3R teleosts into a bioinformatics analysis. Our results suggest that 1, 25D3 acts as a partial agonist in basal species. Furthermore, our bioinformatics analysis suggests that functional differences between VDR orthologs and paralogs are influenced by differential protein interactions with essential coregulator proteins. We speculate that we may be observing a change in the pharmacodynamics relationship between VDR and 1, 25D3 throughout vertebrate evolution that may have been driven by changes in protein-protein interactions between VDR and essential coregulators.

Project description:BackgroundAvian beta-defensins (AvBD) are small, cationic, antimicrobial peptides. The potential application of AvBDs as alternatives to antibiotics has been the subject of interest. However, the mechanisms of action remain to be fully understood. The present study characterized the structure-function relationship of AvBD-6 and AvBD-12, two peptides with different net positive charges, similar hydrophobicity and distinct tissue expression profiles.ResultsAvBD-6 was more potent than AvBD-12 against E. coli, S. Typhimurium, and S. aureus as well as clinical isolates of extended spectrum beta lactamase (ESBL)-positive E. coli and K. pneumoniae. AvBD-6 was more effective than AvBD-12 in neutralizing LPS and interacting with bacterial genomic DNA. Increasing bacterial concentration from 10(5) CFU/ml to 10(9) CFU/ml abolished AvBDs' antimicrobial activity. Increasing NaCl concentration significantly inhibited AvBDs' antimicrobial activity, but not the LPS-neutralizing function. Both AvBDs were mildly chemotactic for chicken macrophages and strongly chemotactic for CHO-K1 cells expressing chicken chemokine receptor 2 (CCR2). AvBD-12 at higher concentrations also induced chemotactic migration of murine immature dendritic cells (DCs). Disruption of disulfide bridges abolished AvBDs' chemotactic activity. Neither AvBDs was toxic to CHO-K1, macrophages, or DCs.ConclusionsAvBDs are potent antimicrobial peptides under low-salt conditions, effective LPS-neutralizing agents, and broad-spectrum chemoattractant peptides. Their antimicrobial activity is positively correlated with the peptides' net positive charges, inversely correlated with NaCl concentration and bacterial concentration, and minimally dependent on intramolecular disulfide bridges. In contrast, their chemotactic property requires the presence of intramolecular disulfide bridges. Data from the present study provide a theoretical basis for the design of AvBD-based therapeutic and immunomodulatory agents.

Project description:Backgroundβ-defensins have attracted considerable research interest because of their roles in protecting hosts from various pathogens. This study was conducted to investigate the expression profiles of the porcine β-defensin 114 (PBD114) in different breeds and in response to infections. Moreover, the function of PBD114 protein was partially investigated.MethodsSix Tibetan pigs (TP) and six DLY (Duroc×Landrace×Yorkshire) pigs were slaughtered to explore the expression profiles of PBD114 in different breeds and tissues. For infection models, sixteen DLY pigs were divided into two groups and challenged either with sterile saline or E. coli K88. The recombinant protein PBD114 (rPBD114) was obtained by using a heterologous expression system in E. coli.ResultsPBD114 gene was highly expressed in tissues such as the intestine, liver, spleen, and thymus. Interestingly, the expression level of PBD114 gene was higher in the TP pigs than in the DLY pigs (P < 0.05), and was significantly elevated upon E. coli K88 challenge (P < 0.05). The nucleotide sequences of PBD114 from Tibetan and DLY pigs was identical, and both showed a 210-bp open reading frame encoding a 69-amino acid mature peptide. To explaore the function of PBD114 protein, PBD114 gene was successfully expressed in E. coli Origami B (DE3) and the molecular weight of the rPBD114 was estimated by SDS-PAGE to be 25 kDa. The rPBD114 was purified and mass spectrometry verified the protein as PBD114. Importantly, rPBD114 showed antimicrobial activities against E. coli DH5α and E. coli K88, and the minimal inhibitory concentrations (MICs) were 64 and 128 μg/mL, respectively. Hemolytic and cytotoxicity assays showed that rPBD114 did not affect cell viability under physiological concentrations.ConclusionsPBD114 is an infection response gene that is differentially-expressed between different porcine breeds and tissues. The antimicrobial activity of PBD114 protein, against pathogens such as the E. coli K88, suggested that it may serve as a candidate for the substitution of conventionally used antibiotics.

Dataset Information

Molecular Evolutionary Analysis of ?-Defensin Peptides in Vertebrates.

Publications

Molecular Evolutionary Analysis of β-Defensin Peptides in Vertebrates.

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