Journal
CELL REPORTS
Volume 13, Issue 6, Pages 1206-1220Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.09.068
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Funding
- Deutsche Forschungsgemeinschaft [SFB 960, FOR2127, KR3901/1-2, KR3901/2-1]
- European Research Council [242792]
- Bavarian Genome Research Network (BayGene)
- Bavarian Systems-Biology Network (BioSysNet)
- CIHR
- European Research Council (ERC) [242792] Funding Source: European Research Council (ERC)
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TRIM-NHL proteins are conserved among metazoans and control cell fate decisions in various stem cell linages. The Drosophila TRIM-NHL protein Brain tumor (Brat) directs differentiation of neuronal stem cells by suppressing self-renewal factors. Brat is an RNA-binding protein and functions as a translational repressor. However, it is unknown which RNAs Brat regulates and how RNA-binding specificity is achieved. Using RNA immunoprecipitation and RNAcompete, we identify Brat-bound mRNAs in Drosophila embryos and define consensus binding motifs for Brat as well as a number of additional TRIM-NHL proteins, indicating that TRIM-NHL proteins are conserved, sequence-specific RNA-binding proteins. We demonstrate that Brat-mediated repression and direct RNA-binding depend on the identified motif and show that binding of the localization factor Miranda to the Brat-NHL domain inhibits Brat activity. Finally, to unravel the sequence specificity of the NHL domain, we crystallize the BratNHL domain in complex with RNA and present a high-resolution protein-RNA structure of this fold.
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