Department of Biochemistry and Molecular Pharmacology
Allosteric Site; Amino Acid Motifs; Animals; Cell Differentiation; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation; Mice; Molecular Dynamics Simulation; Nerve Tissue Proteins; Oleic Acid; Pluripotent Stem Cells; Protein Structure, Tertiary; RNA-Binding Proteins; Recombinant Proteins; Stearoyl-CoA Desaturase; Stem Cells; Structure-Activity Relationship
Biochemistry | Biochemistry, Biophysics, and Structural Biology | Biophysics | Genetics and Genomics | Genomics | Structural Biology
Gene expression and metabolism are coupled at numerous levels. Cells must sense and respond to nutrients in their environment, and specialized cells must synthesize metabolic products required for their function. Pluripotent stem cells have the ability to differentiate into a wide variety of specialized cells. How metabolic state contributes to stem cell differentiation is not understood. In this study, we show that RNA-binding by the stem cell translation regulator Musashi-1 (MSI1) is allosterically inhibited by 18-22 carbon omega-9 monounsaturated fatty acids. The fatty acid binds to the N-terminal RNA Recognition Motif (RRM) and induces a conformational change that prevents RNA association. Musashi proteins are critical for development of the brain, blood, and epithelium. We identify stearoyl-CoA desaturase-1 as a MSI1 target, revealing a feedback loop between omega-9 fatty acid biosynthesis and MSI1 activity. We propose that other RRM proteins could act as metabolite sensors to couple gene expression changes to physiological state.
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Citation: Elife. 2014 Jun 16;3:e02848. doi: 10.7554/eLife.02848. Link to article on publisher's site
DOI of Published Version
RNA-binding protein, biochemistry, biophysics, gene expression, metabolism, oligodendrocyte, post-transcriptional regulation, structural biology
Clingman, Carina C.; Deveau, Laura M.; Hay, Samantha A.; Genga, Ryan M. J.; Shandilya, Shivender; Massi, Francesca; and Ryder, Sean P., "Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite" (2014). Open Access Articles. 2553.
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