As a worldwide sanitary insect pest, the housefly Musca domestica can carry and transmit more than 100 human pathogens without suffering any illness itself, indicative of the high efficiency of its innate immune system. Antimicrobial peptides (AMPs) are the effectors of the innate immune system of multicellular organisms and establish the first line of defense to protect hosts from microbial infection. To explore the molecular diversity of the M. domestica AMPs and related evolutionary basis, we conducted a systematic survey of its full AMP components based on a combination of computational approaches. These components include the cysteine-containing peptides (MdDefensins, MdEppins, MdMuslins, MdSVWCs and MdCrustins), the linear α-helical peptides (MdCecropins) and the specific amino acid-rich peptides (MdDomesticins, MdDiptericins, MdEdins and MdAttacins). On this basis, we identified multiple genetic mechanisms that could have shaped the molecular and structural diversity of the M. domestica AMPs, including: (1) Gene duplication; (2) Exon duplication via shuffling; (3) Protein terminal variations; (4) Evolution of disulfide bridges via compensation. Our results not only enlarge the insect AMP family members, but also offer a basic platform for further studying the roles of such molecular diversity in contributing to the high efficiency of the housefly antimicrobial immune system.
Defensins are a class of cationic disulfide-bridged antimicrobial peptides (AMPs) present in many eukaryotic organisms and even in bacteria. They primarily include two distinct but evolutionarily related superfamilies (cis and trans). Defensins in fungi belong to the members of the cis-superfamily with the cysteine-stabilized α-helical and β-sheet fold. To date, many fungal defensin-like peptides (fDLPs) have been found through gene mining of the genome resource, but only a few have been experimentally characterized. Here, we report the structural and functional characterization of Pyronesin4 (abbreviated as Py4), a fDLP previously identified by genomic sequencing of the basal filamentous ascomycete Pyronema confluens. Chemically, synthetic Py4 adopts a native-like structure and exhibits activity on an array of Gram-positive bacteria including some clinical isolates of Staphylococcus and Staphylococcus warneri, a conditioned pathogen inhabiting in human skin. Py4 markedly altered the bacterial morphology and caused cytoplasmic accumulation of the cell-wall synthesis precursor through binding to the membrane-bound Lipid II, indicating that it works as an inhibitor of cell-wall biosynthesis. Py4 showed no hemolysis and high mammalian serum stability. This work identified a new fungal defensin with properties relevant to drug exploration. Intramolecular epistasis between mutational sites of fDLPs is also discussed.
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