Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo
| Autor: | Pavlovic, Igor, Thakor, Divyeshsinh T, Vargas, Jessica R, McKinlay, Colin J, Hauke, Sebastian, Anstaett, Philipp, Camuña, Rafael C, Bigler, Laurent, Gasser, Gilles, Schultz, Carsten, Wender, Paul A, Jessen, Henning J |
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| Přispěvatelé: | University of Zurich, Wender, Paul A |
| Rok vydání: | 2015 |
| Předmět: |
10120 Department of Chemistry
Cytoplasm Magnetic Resonance Spectroscopy Microscopy Confocal Science Inositol Phosphates Cell Membrane 1600 General Chemistry Flow Cytometry Photochemical Processes 3100 General Physics and Astronomy Article Nanostructures Protein Structure Tertiary Drug Delivery Systems Microscopy Fluorescence 1300 General Biochemistry Genetics and Molecular Biology Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization 540 Chemistry Humans Nanoparticles Proto-Oncogene Proteins c-akt HeLa Cells Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-8 (2016) |
| ISSN: | 2041-1723 |
| Popis: | Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP7), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP7 and caged InsP7. The caged molecule is stable and releases InsP7 only on irradiation. While photocaged InsP7 does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP7 signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP7 leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm. Photocaged inositol-pyrophosphates offer a tool to study cellular signalling, but their challenging synthesis has precluded any biological studies so far. Here, the authors report the synthesis and cellular delivery of a photocaged analogue, and show that it mediates protein translocation in cellulo. |
| Databáze: | OpenAIRE |
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