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Allosteric inhibition of a stem cell RNA‐binding protein by an intermediary metabolite
Author(s) -
Ryder Sean P,
Clingman Carina C,
Deveau Laura M,
Massi Francesca
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.745.3
Subject(s) - microbiology and biotechnology , biochemistry , stem cell , rna binding protein , rna , progenitor cell , biology , induced pluripotent stem cell , fatty acid , gene expression , cell , allosteric regulation , gene , chemistry , embryonic stem cell , enzyme
Gene expression and metabolism are coupled at numerous levels. Cells must sense and accurately respond to the nutrients in their environment, and specialized cells must synthesize the metabolic products required for their function. Pluripotent stem cells have the ability to differentiate into a wide variety of specialized cells. Exactly how metabolic state contributes to stem cell differentiation is the subject of intense investigation. Here, we show that the RNA‐binding activity of the stem cell translational regulator Musashi‐1 (MSI1) is allosterically inhibited by non‐esterified 18–22 carbon cis ω‐9 monounsaturated fatty acids. Inhibition is direct and highly specific. The fatty acid binds to the N‐terminal RNA Recognition Motif (RRM) and induces a conformational change that prevents RNA association. Musashi‐family proteins are critical for development of the brain, blood, and epithelial lineages, and play an important role in maintaining the viability of oligodendrocyte progenitor cells (OPCs). We identify stearoyl‐CoA desaturase 1 as a MSI1 target, revealing a feedback loop between ω‐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.