title: Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite.
abstract: 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 ω-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 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Carina C
authors.initials: CC
authors.lastname: Clingman
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Deveau
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Hay
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Genga
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Shivender M D
authors.initials: SM
authors.lastname: Shandilya
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Massi
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ryder
mesh_terms: D000495:Allosteric Site; D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019301:Oleic Acid / Q000737:chemistry*; D039904:Pluripotent Stem Cells / Q000166:cytology; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D013329:Structure-Activity Relationship
chemical_list: C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D019301:Oleic Acid; D013230:Stearoyl-CoA Desaturase
keywords: RNA-binding protein; biochemistry; biophysics; gene expression; metabolism; none; oligodendrocyte; post-transcriptional regulation; structural biology