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Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):E6757-E6765. Epub 2016 Oct 19.

Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms.

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Department of Chemistry, Princeton University, Princeton, NJ 08544.
Division of Neurosurgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Department of Chemical Biology, Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
Department of Chemistry, Princeton University, Princeton, NJ 08544;


Inositol-based signaling molecules are central eukaryotic messengers and include the highly phosphorylated, diffusible inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs). Despite the essential cellular regulatory functions of InsPs and PP-InsPs (including telomere maintenance, phosphate sensing, cell migration, and insulin secretion), the majority of their protein targets remain unknown. Here, the development of InsP and PP-InsP affinity reagents is described to comprehensively annotate the interactome of these messenger molecules. By using the reagents as bait, >150 putative protein targets were discovered from a eukaryotic cell lysate (Saccharomyces cerevisiae). Gene Ontology analysis of the binding partners revealed a significant overrepresentation of proteins involved in nucleotide metabolism, glucose metabolism, ribosome biogenesis, and phosphorylation-based signal transduction pathways. Notably, we isolated and characterized additional substrates of protein pyrophosphorylation, a unique posttranslational modification mediated by the PP-InsPs. Our findings not only demonstrate that the PP-InsPs provide a central line of communication between signaling and metabolic networks, but also highlight the unusual ability of these molecules to access two distinct modes of action.


affinity reagents; inositol pyrophosphates; metabolism; protein pyrophosphorylation; signal transduction

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