Forschungsschwerpunkte

Mechanischer Stress

Wir utnersuchen systematisch Proteinkinase- und Proteinphosphatase-abhängige Signalnetzwerke in Säugetierzellen, um komplizierte Substrat-Kinase/-Phosphatase-Beziehungen auf systemweiter Ebene zu entschlüsseln. Wir interessieren uns hier insbesondere für Signalprozesse beim Schutz vor mechanischer Belastung.

Letzte Publikationen

Fricke, A. L., Mühlhäuser, W. W. D., Reimann, L., Zimmermann, J. P., Reichenbach, C., Knapp, B., Peikert, C. D., Heberle, A. M., Faessler, E., Schäuble, S., Hahn, U., Thedieck, K., Radziwill, G., & Warscheid, B. (2023). Phosphoproteomics Profiling Defines a Target Landscape of the Basophilic Protein Kinases AKT, S6K, and RSK in Skeletal Myotubes. Journal of Proteome Research, 22(3), 768-789. https://doi.org/10.1021/acs.jproteome.2c00505
- [ Abstract ]
- [ DOI ]
Phosphorylation-dependent signal transduction plays an important role in regulating the functions and fate of skeletal muscle cells. Central players in the phospho-signaling network are the protein kinases AKT, S6K, and RSK as part of the PI3K-AKT-mTOR-S6K and RAF-MEK-ERK-RSK pathways. However, despite their functional importance, knowledge about their specific targets is incomplete because these kinases share the same basophilic substrate motif RxRxxp[ST]. To address this, we performed a multifaceted quantitative phosphoproteomics study of skeletal myotubes following kinase inhibition. Our data corroborate a cross talk between AKT and RAF, a negative feedback loop of RSK on ERK, and a putative connection between RSK and PI3K signaling. Altogether, we report a kinase target landscape containing 49 so far unknown target sites. AKT, S6K, and RSK phosphorylate numerous proteins involved in muscle development, integrity, and functions, and signaling converges on factors that are central for the skeletal muscle cytoskeleton. Whereas AKT controls insulin signaling and impinges on GTPase signaling, nuclear signaling is characteristic for RSK. Our data further support a role of RSK in glucose metabolism. Shared targets have functions in RNA maturation, stability, and translation, which suggests that these basophilic kinases establish an intricate signaling network to orchestrate and regulate processes involved in translation.

Förderung

Deutsche Forschungsgemeinschaft
- FOR 2743 (WA1598/6)
- TRR 130
Exzellenzstratgie
- CIBSS─EXC-2189 (project ID 390939984)

Mitochondrien bei Gesundheit und Krankheit

Letzte Publikationen

Morgenstern, M., Stiller, S. B., Lübbert, P., Peikert, C. D., Dannenmaier, S., Drepper, F., Weill, U., Höß, P., Feuerstein, R., Gebert, M., Bohnert, M., van der Laan, M., Schuldiner, M., Schütze, C., Oeljeklaus, S., Pfanner, N., Wiedemann, N., & Warscheid, B. (2017). Definition of a High-Confidence Mitochondrial Proteome at Quantitative Scale. Cell Reports, 19(13), 2836-2852. https://doi.org/10.1016/j.celrep.2017.06.014
- [ Abstract ]
- [ DOI ]
Mitochondria perform central functions in cellular bioenergetics, metabolism, and signaling, and their dysfunction has been linked to numerous diseases. The available studies cover only part of the mitochondrial proteome, and a separation of core mitochondrial proteins from associated fractions has not been achieved. We developed an integrative experimental approach to define the proteome~of yeast mitochondria. We classified {$$>$$ 3,300 proteins of mitochondria and mitochondria-associated fractions and defined 901 high-confidence mitochondrial proteins, expanding the set of mitochondrial proteins by 82. Our analysis includes~protein abundance under fermentable and nonfermentable growth, submitochondrial localization, single-protein~experiments, and subcellular classification of mitochondria-associated fractions. We identified mitochondrial interactors of respiratory chain supercomplexes, ATP synthase, AAA proteases, the mitochondrial contact site and cristae organizing system (MICOS), and the coenzyme Q biosynthesis cluster, as well as mitochondrial proteins with dual cellular localization. The integrative proteome provides a high-confidence~source for the characterization of physiological and pathophysiological functions of mitochondria and their integration into the cellular environment.

Förderung

Peroxisomaler Proteinimport

Letzte Publikationen

Chen, W. W., Rodrigues, T. A., Wendscheck, D., Pedrosa, A. G., Yang, C., Francisco, T., Möcklinghoff, T., Zografakis, A., Nunes-Silva, B., Avraham, R. E., Silva, A. R., Ferreira, M. J., Das, H., Bender, J., Oeljeklaus, S., Sondhi, V., Schuldiner, M., Zalckvar, E., Hofmann, K., … Warscheid, B. (2024). PEX39 facilitates the peroxisomal import of PTS2 proteins. https://doi.org/10.1101/2024.04.30.591961
- [ DOI ]
Lill, P., Hansen, T., Wendscheck, D., Klink, B. U., Jeziorek, T., Vismpas, D., Miehling, J., Bender, J., Schummer, A., Drepper, F., Girzalsky, W., Warscheid, B., Erdmann, R., & Gatsogiannis, C. (2020). Towards the Molecular Architecture of the Peroxisomal Receptor Docking Complex. Proceedings of the National Academy of Sciences of the United States of America, 117(52), 33216-33224. https://doi.org/10.1073/pnas.2009502117
- [ Abstract ]
- [ DOI ]
Import of yeast peroxisomal matrix proteins is initiated by cytosolic receptors, which specifically recognize and bind the respective cargo proteins. At the peroxisomal membrane, the cargo-loaded receptor interacts with the docking protein Pex14p that is tightly associated with Pex17p. Previous data suggest that this interaction triggers the formation of an import pore for further translocation of the cargo. The mechanistic principles, however, are unclear, mainly because structures of higher-order assemblies are still lacking. Here, using an integrative approach, we provide the structural characterization of the major components of the peroxisomal docking complex Pex14p/Pex17p, in a native bilayer environment, and reveal its subunit organization. Our data show that three copies of Pex14p and a single copy of Pex17p assemble to form a 20-nm rod-like particle. The different subunits are arranged in a parallel manner, showing interactions along their complete sequences and providing receptor binding sites on both membrane sides. The long rod facing the cytosol is mainly formed by the predicted coiled-coil domains of Pex14p and Pex17p, possibly providing the necessary structural support for the formation of the import pore. Further implications of Pex14p/Pex17p for formation of the peroxisomal translocon are discussed.

Förderung

Hubland Süd, Geb. B1

Hubland Nord, Geb. 32 Julius-von-Sachs-Platz 2 Fabrikschleichach Hubland Süd, Geb. B2 Campus Medizin

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