Pharmacological perturbation of the phase-separating protein SMNDC1.

Autor: Enders L; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Siklos M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Borggräfe J; Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Neuherberg, 85764, München, Germany.; Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center, Garching, 85748, München, Germany., Gaussmann S; Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Neuherberg, 85764, München, Germany.; Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center, Garching, 85748, München, Germany., Koren A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Malik M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Tomek T; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Schuster M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Reiniš J; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Hahn E; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Rukavina A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Reicher A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Casteels T; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria.; Sloan Kettering Institute, 1275 York Avenue, New York, NY, 10065, USA., Bock C; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria.; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Währinger Straße 25a, 1090, Vienna, Austria., Winter GE; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Hannich JT; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria., Sattler M; Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Neuherberg, 85764, München, Germany.; Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center, Garching, 85748, München, Germany., Kubicek S; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090, Vienna, Austria. skubicek@cemm.oeaw.ac.at.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Aug 16; Vol. 14 (1), pp. 4504. Date of Electronic Publication: 2023 Aug 16.
DOI: 10.1038/s41467-023-40124-0
Abstrakt: SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminal region of SMNDC1, depends on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein's Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes for SMNDC1-dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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