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Enders, L.* ; Siklos, M.* ; Borggräfe, J. ; Gaussmann, S. ; Koren, A.* ; Malik, M.* ; Tomek, T.* ; Schuster, M.* ; Reiniš, J.* ; Hahn, E.* ; Rukavina, A.* ; Reicher, A.* ; Casteels, T.* ; Bock, C.* ; Winter, G.E.* ; Hannich, J.T.* ; Sattler, M. ; Kubicek, S.*

Pharmacological perturbation of the phase-separating protein SMNDC1.

Nat. Commun. 14:4504 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 14, Issue: 1, Pages: , Article Number: 4504 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)