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Pharmacological perturbation of the phase-separating protein SMNDC1

ABSTRACT: SMNDC1 is an essential splicing factor that, like its better-studied paralog SMN, binds to di-methylated arginines using its Tudor domain. The specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function have not been studied in detail. Here, we perform such analysis and develop first small molecule inhibitors targeting the dimethyl arginine 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-terminus, dependent 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 at 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Andrea Rukavina

LAB HEAD: Stefan Kubicek

PROVIDER: PXD037092 | Pride | 2023-09-04

REPOSITORIES: Pride

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