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. Here, 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.
Article and author information
Author details
Reviewing Editor
- Douglas L Black, Howard Hughes Medical Institute, University of California, Los Angeles, United States
Version history
- Received: March 19, 2014
- Accepted: June 15, 2014
- Accepted Manuscript published: June 16, 2014 (version 1)
- Version of Record published: July 15, 2014 (version 2)
Copyright
© 2014, Clingman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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