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Peer-reviewedCC BYNature Communications

Proteome-wide quantification of inositol pyrophosphate-protein interactions

  • Annika Richter1,2,3,4
  • Jaime A. Isern2,4
  • Max Ruwolt2,3,4
  • Sarah Lampe1,2,5,4
  • Abhirup Majumdar1,2,3,4
  • Fan Liu6,2,3,4
  • David Furkert7,8
  • Dorothea Fiedler9,10
10 affiliations
  1. 1Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße 2, Berlin, Germany
  2. 2Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, Berlin, Germany
  3. 3Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße , 1489 Berlin, Germany
  4. 4Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 0, 325 Berlin, Germany
  5. 5Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
  6. 6Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany
  7. 7Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße 2, Berlin, Germany. [email protected]
  8. 8Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, Berlin, Germany. [email protected]
  9. 9Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße 2, Berlin, Germany. [email protected]
  10. 10Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, Berlin, Germany. [email protected]
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Abstract

Inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs) constitute a group of highly phosphorylated molecules that are involved in many cellular signaling processes. To characterize discrete signaling events of these structurally closely related molecules, a mass spectrometry approach was developed to derive apparent binding constants for these ligands on a proteome-wide scale. The method employed a series of chemically synthesized, biotinylated affinity reagents for inositol hexakisphosphate (InsP 6 ), and the inositol pyrophosphates 1PP-InsP 5 , 5PP-InsP 5 and 1,5(PP) 2 -InsP 4 (also termed InsP 8 ). Application of these affinity reagents at different concentrations, in combination with tandem mass tag (TMT) labeling, provided binding data for thousands of proteins from a mammalian cell lysate. Investigation of different enrichment conditions, where Mg 2+ ions were either available or not, showcased a strong influence of Mg 2+ on the protein binding capacities of PP-InsPs. Gene ontology analysis closely linked PP-InsP-interacting proteins to RNA processing in the nucleus and nucleolus. Subsequent data analysis enabled a targeted search for protein pyrophosphorylation among PP-InsP interactors, and identified four new pyrophosphorylated proteins. The data presented here constitute a valuable resource for the community, and application of the method reported here to other biological contexts will enable the exploration of PP-InsP dependent signaling pathways across species.

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Cite

BibTeXRIS
BibTeX
@article{richter2026proteomewide,
  title = {{Proteome-wide quantification of inositol pyrophosphate-protein interactions}},
  author = {Annika Richter and Jaime A. Isern and Max Ruwolt and Sarah Lampe and Abhirup Majumdar and Fan Liu and David Furkert and Dorothea Fiedler},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-73804-8},
  url = {https://doi.org/10.1038/s41467-026-73804-8},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Proteome-wide quantification of inositol pyrophosphate-protein interactions
AU  - Annika Richter
AU  - Jaime A. Isern
AU  - Max Ruwolt
AU  - Sarah Lampe
AU  - Abhirup Majumdar
AU  - Fan Liu
AU  - David Furkert
AU  - Dorothea Fiedler
PY  - 2026
DA  - 2026/06/04
JO  - Nature Communications
DO  - 10.1038/s41467-026-73804-8
UR  - https://doi.org/10.1038/s41467-026-73804-8
AB  - Inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs) constitute a group of highly phosphorylated molecules that are involved in many cellular signaling processes. To characterize discrete signaling events of these structurally closely related molecules, a mass spectrometry approach was developed to derive apparent binding constants for these ligands on a proteome-wide scale. The method employed a series of chemically synthesized, biotinylated affinity reagents for inositol hexakisphosphate (InsP 6 ), and the inositol pyrophosphates 1PP-InsP 5 , 5PP-InsP 5 and 1,5(PP) 2 -InsP 4 (also termed InsP 8 ). Application of these affinity reagents at different concentrations, in combination with tandem mass tag (TMT) labeling, provided binding data for thousands of proteins from a mammalian cell lysate. Investigation of different enrichment conditions, where Mg 2+ ions were either available or not, showcased a strong influence of Mg 2+ on the protein binding capacities of PP-InsPs. Gene ontology analysis closely linked PP-InsP-interacting proteins to RNA processing in the nucleus and nucleolus. Subsequent data analysis enabled a targeted search for protein pyrophosphorylation among PP-InsP interactors, and identified four new pyrophosphorylated proteins. The data presented here constitute a valuable resource for the community, and application of the method reported here to other biological contexts will enable the exploration of PP-InsP dependent signaling pathways across species.
SN  - 2041-1723
ER  -