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RAMPing Up Stress Signaling: Protein AMPylation in Metazoans.

ABSTRACT: Protein AMPylation - the covalent attachment of an AMP residue to amino acid side chains using ATP as the donor - is a post-translational modification (PTM) increasingly appreciated as relevant for both normal and pathological cell signaling. In metazoans single copies of filamentation induced by cAMP (fic)-domain-containing AMPylases - the enzymes responsible for AMPylation - preferentially modify a set of dedicated targets and contribute to the perception of cellular stress and its regulation. Pathogenic bacteria can exploit AMPylation of eukaryotic target proteins to rewire host cell signaling machinery in support of their propagation and survival. We review endogenous as well as parasitic protein AMPylation in metazoans and summarize current views of how fic-domain-containing AMPylases contribute to cellular proteostasis.

SUBMITTER: Truttmann MC

PROVIDER: S-EPMC5524611 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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rAMPing Up Stress Signaling: Protein AMPylation in Metazoans.

Truttmann Matthias C MC Ploegh Hidde L HL

Trends in cell biology 20170419 8

Protein AMPylation - the covalent attachment of an AMP residue to amino acid side chains using ATP as the donor - is a post-translational modification (PTM) increasingly appreciated as relevant for both normal and pathological cell signaling. In metazoans single copies of filamentation induced by cAMP (fic)-domain-containing AMPylases - the enzymes responsible for AMPylation - preferentially modify a set of dedicated targets and contribute to the perception of cellular stress and its regulation. ...[more]

PMID: 28433487

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Project description:BackgroundUncovering novel components of signal transduction pathways and their interactions within species is a central task in current biological research. Orthology alignment and functional genomics approaches allow the effective identification of signaling proteins by cross-species data integration. Recently, functional annotation of orthologs was transferred across organisms to predict novel roles for proteins. Despite the wide use of these methods, annotation of complete signaling pathways has not yet been transferred systematically between species.Principal findingsHere we introduce the concept of 'signalog' to describe potential novel signaling function of a protein on the basis of the known signaling role(s) of its ortholog(s). To identify signalogs on genomic scale, we systematically transferred signaling pathway annotations among three animal species, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and humans. Using orthology data from InParanoid and signaling pathway information from the SignaLink database, we predict 88 worm, 92 fly, and 73 human novel signaling components. Furthermore, we developed an on-line tool and an interactive orthology network viewer to allow users to predict and visualize components of orthologous pathways. We verified the novelty of the predicted signalogs by literature search and comparison to known pathway annotations. In C. elegans, 6 out of the predicted novel Notch pathway members were validated experimentally. Our approach predicts signaling roles for 19 human orthodisease proteins and 5 known drug targets, and suggests 14 novel drug target candidates.ConclusionsOrthology-based pathway membership prediction between species enables the identification of novel signaling pathway components that we referred to as signalogs. Signalogs can be used to build a comprehensive signaling network in a given species. Such networks may increase the biomedical utilization of C. elegans and D. melanogaster. In humans, signalogs may identify novel drug targets and new signaling mechanisms for approved drugs.

Dataset Information

RAMPing Up Stress Signaling: Protein AMPylation in Metazoans.

Publications

rAMPing Up Stress Signaling: Protein AMPylation in Metazoans.

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