Dataset Information

Unifying structural signature of eukaryotic ?-helical host defense peptides.

ABSTRACT: Diversity of ?-helical host defense peptides (?HDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among ?HDPs is inherently difficult, even for artificial-intelligence-based methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic ?HDPs derived from amino acid sequence, biochemical, and three-dimensional properties of known ?HDPs. The signature formula contains a helical domain of 12 residues with a mean hydrophobic moment of 0.50 and favoring aliphatic over aromatic hydrophobes in 18-aa windows of peptides or proteins matching its semantic definition. The holistic ?-core signature subsumes existing physicochemical properties of ?HDPs, and converged strongly with predictions of an independent machine-learning-based classifier recognizing sequences inducing negative Gaussian curvature in target membranes. Queries using the ?-core formula identified 93% of all annotated ?HDPs in proteomic databases and retrieved all major ?HDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying ?-core signature establishes a foundational framework for discovering and understanding ?HDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.

SUBMITTER: Yount NY

PROVIDER: S-EPMC6452647 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Unifying structural signature of eukaryotic α-helical host defense peptides.

Yount Nannette Y NY Weaver David C DC Lee Ernest Y EY Lee Michelle W MW Wang Huiyuan H Chan Liana C LC Wong Gerard C L GCL Yeaman Michael R MR

Proceedings of the National Academy of Sciences of the United States of America 20190315 14

Diversity of α-helical host defense peptides (αHDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among αHDPs is inherently difficult, even for artificial-intelligence-based methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic αHDPs derived from amino acid sequence, ...[more]

PMID: 30877253

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Project description:Host defense caerin 1.1 and 1.9 peptides, isolated from the glandular secretion of Australian tree frogs, the genus Litoria, have been previously shown to have multiple biological activities, including the inhibition of human papillomavirus (HPV) 16 early protein E7 transformed murine as well as human cancerous cell proliferation both in vitro and in vivo. However, the mechanism underlying their anti-proliferative activities against HPV18+ cervical cancer HeLa cells remains unknown. This study comparatively investigated the anti-proliferation on HeLa cells by caerin 1.1, 1.9, and their mixture, followed by confocal microscopy examination to assess the cellular intake of the peptides. Tandem mass tag labeling proteomics was employed to reveal the proteins that were significantly regulated by the peptide treatment in cells and cell growth environment, to elucidate the signaling pathways that were modulated. Western blot was performed to confirm the modulation of the pathways. Both caerin 1.1 and 1.9 highly inhibited HeLa cell proliferation with a significant additive effect compared to untreated and control peptide. They entered the cells with different magnitudes. Intensive protein-protein interaction was detected among significantly upregulated proteins. Translation, folding and localization of proteins and RNA processing, apoptosis process was significantly enriched post the treatments. The apoptotic signaling was suggested as a result of tumor necrosis factor-? (TNF-?) pathway activation, indicated by the dose-dependent elevated levels of caspase 3 and caspase 9. The epidermal growth factor receptor and androgen receptor pathways appeared inhibited by the peptides. Moreover, the activation of T-cell receptor derived from the quantitation results further implies the likelihood of recruiting more T cells to the cell growth environment post the treatment and more sensitive to T cell mediated killing of HeLa cells. Our results indicate that caerin 1.1 and 1.9 mediate apoptotic signals of HeLa cells and may subsequently enhances adaptive T cell immune responses.

Dataset Information

Unifying structural signature of eukaryotic ?-helical host defense peptides.

Publications

Unifying structural signature of eukaryotic α-helical host defense peptides.

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