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Structure, function, and evolution of Gga-AvBD11, the archetype of the structural avian-double-?-defensin family.

ABSTRACT: Out of the 14 avian ?-defensins identified in the Gallus gallus genome, only 3 are present in the chicken egg, including the egg-specific avian ?-defensin 11 (Gga-AvBD11). Given its specific localization and its established antibacterial activity, Gga-AvBD11 appears to play a protective role in embryonic development. Gga-AvBD11 is an atypical double-sized defensin, predicted to possess 2 motifs related to ?-defensins and 6 disulfide bridges. The 3-dimensional NMR structure of the purified Gga-AvBD11 is a compact fold composed of 2 packed ?-defensin domains. This fold is the archetype of a structural family, dubbed herein as avian-double-?-defensins (Av-DBD). We speculate that AvBD11 emanated from a monodomain gene ancestor and that similar events might have occurred in arthropods, leading to another structural family of less compact DBDs. We show that Gga-AvBD11 displays antimicrobial activities against gram-positive and gram-negative bacterial pathogens, the avian protozoan Eimeria tenella, and avian influenza virus. Gga-AvBD11 also shows cytotoxic and antiinvasive activities, suggesting that it may not only be involved in innate protection of the chicken embryo, but also in the (re)modeling of embryonic tissues. Finally, the contribution of either of the 2 Gga-AvBD11 domains to these biological activities was assessed, using chemically synthesized peptides. Our results point to a critical importance of the cationic N-terminal domain in mediating antibacterial, antiparasitic, and antiinvasive activities, with the C-terminal domain potentiating the 2 latter activities. Strikingly, antiviral activity in infected chicken cells, accompanied by marked cytotoxicity, requires the full-length protein.

SUBMITTER: Guyot N

PROVIDER: S-EPMC6955361 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Structure, function, and evolution of Gga-AvBD11, the archetype of the structural avian-double-β-defensin family.

Guyot Nicolas N Meudal Hervé H Trapp Sascha S Iochmann Sophie S Silvestre Anne A Jousset Guillaume G Labas Valérie V Reverdiau Pascale P Loth Karine K Hervé Virginie V Aucagne Vincent V Delmas Agnès F AF Rehault-Godbert Sophie S Landon Céline C

Proceedings of the National Academy of Sciences of the United States of America 20191223 1

Out of the 14 avian β-defensins identified in the Gallus gallus genome, only 3 are present in the chicken egg, including the egg-specific avian β-defensin 11 (Gga-AvBD11). Given its specific localization and its established antibacterial activity, Gga-AvBD11 appears to play a protective role in embryonic development. Gga-AvBD11 is an atypical double-sized defensin, predicted to possess 2 motifs related to β-defensins and 6 disulfide bridges. The 3-dimensional NMR stru ...[more]

PMID: 31871151

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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:BACKGROUND:?-defensins and cathelicidins are two families of cationic antimicrobial peptides (AMPs) with a broad range of antimicrobial activities that are key components of the innate immune system. Due to their important roles in host defense against rapidly evolving pathogens, the two gene families provide an ideal system for studying adaptive gene evolution. In this study we performed phylogenetic and selection analyses on ?-defensins and cathelicidins from 53 avian species representing 32 orders to examine the evolutionary dynamics of these peptides in birds. RESULTS AND CONCLUSIONS:Avian ?-defensins are found in a gene cluster consisting of 13 subfamiles. Nine of these are conserved as one to one orthologs in all birds, while the others (AvBD1, AvBD3, AvBD7 and AvBD14) are more subject to gene duplication or pseudogenisation events in specific avian lineages. Avian cathelicidins are found in a gene cluster consisting of three subfamilies with species-specific duplications and gene loss. Evidence suggested that the propiece and mature peptide domains of avian cathelicidins are possibly co-evolving in such a way that the cationicity of the mature peptide is partially neutralised by the negative charge of the propiece prior to peptide secretion (further evidence obtained by repeating the analyses on primate cathelicidins). Negative selection (overall mean dN < dS) was detected in most of the gene domains examined, conserving certain amino acid residues that may be functionally crucial for the avian ?-defensins and cathelicidins, while episodic positive selection was also involved in driving the diversification of specific codon sites of certain AMPs in avian evolutionary history. These findings have greatly improved our understanding of the molecular evolution of avian AMPs and will be useful to understand their role in the avian innate immune response. Additionally, the large dataset of ?-defensin and cathelicidin peptides may also provide a valuable resource for translational research and development of novel antimicrobial agents in the future.

Project description:The primate ?-/?-defensin multigene family encodes versatile endogenous cationic and amphipathic peptides that have broad-spectrum antibacterial, antifungal and antiviral activity. Although previous studies have reported that ?-/?-defensin (DEFA/DEFT) genes are under birth-and-death evolution with frequent duplication and rapid evolution, the phylogenetic relationships of the primate DEFA/DEFT genes; the genetic bases for the existence of similar antimicrobial spectra among closely related species; and the evolutionary processes involved in the emergence of cyclic ?-defensins in Old World monkeys and their subsequent loss of function in humans, chimpanzees and gorillas require further investigation. In this study, the DEFA/DEFT gene repertoires from primate and treeshrew were collected, followed by detailed phylogenetic, sequence and structure, selection pressure and comparative genomics analyses. All treeshrew, prosimian and simian DEFA/DEFT genes are grouped into two major clades, which are tissue-specific for enteric and myeloid defensins in simians. The simian enteric and myeloid ?-defensins are classified into six functional gene clusters with diverged sequences, variable structures, altered functional constraints and different selection pressures, which likely reflect the antimicrobial spectra among closely related species. Species-specific duplication or pseudogenization within each simian cluster implies that the antimicrobial spectrum is ever-shifting, most likely challenged by the ever-changing pathogen environment. The DEFT evolved from the myeloid DEFA8. The prosegment of ?-defensin is detected with adaptive changes coevolving with the new protein fold of mature peptide, coincident with the importance of the prosegment for the correct folding of the mature peptide. Lastly, a less-is-hitchhiking hypothesis was proposed as a possible explanation for the expansion of pseudogene DEFTP and the loss of functional DEFT, where the gain or loss of the hitchhiker is determined by its adjacent driver gene during the birth-and-death evolutionary process.

Dataset Information

Structure, function, and evolution of Gga-AvBD11, the archetype of the structural avian-double-?-defensin family.

Publications

Structure, function, and evolution of <i>Gga</i>-AvBD11, the archetype of the structural avian-double-β-defensin family.

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