Structure and Function of Steroid Receptor RNA Activator Protein, the Proposed Partner of SRA Noncoding RNA

被引:24
作者
McKay, David B. [1 ,2 ,3 ]
Xi, Linghe [1 ,4 ]
Barthel, Kristen K. B. [1 ,4 ]
Cech, Thomas R. [1 ,2 ,3 ,4 ]
机构
[1] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA
[2] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA
[3] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA
[4] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA
基金
美国国家卫生研究院;
关键词
estrogen; nuclear receptor; RNA-binding protein; transcription factor; steroid receptor activator; DIFFRACTION DATA; CANCER CELLS; EXPRESSION; ALPHA; COACTIVATION; BINDING; TRANSCRIPTION; SYSTEM; MOTIFS; BETA;
D O I
10.1016/j.jmb.2014.01.006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In a widely accepted model, the steroid receptor RNA activator protein (SRA protein; SRAP) modulates the transcriptional regulatory activity of SRA RNA by binding a specific stem-loop of SRA. We first confirmed that SRAP is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, where it is expressed at the level of about 105 molecules per cell. However, our SRAP-RNA binding experiments, both in vitro with recombinant protein and in cultured cells with plasmid-expressed protein and RNA, did not reveal a specific interaction between SRAP and SRA. We determined the crystal structure of the carboxyterminal domain of human SRAP and found that it does not have the postulated RRM (RNA recognition motif). The structure is a five-helix bundle that is distinct from known RNA-binding motifs and instead is similar to the carboxy-terminal domain of the yeast spliceosome protein PRP18, which stabilizes specific protein-protein interactions within a multisubunit mRNA splicing complex. SRA binding experiments with this domain gave negative results. Transcriptional regulation by SRA/SRAP was examined with siRNA knockdown. Effects on both specific estrogen-responsive genes and genes identified by RNA-seq as candidates for regulation were examined in MCF-7 cells. Only a small effect (similar to 20% change) on one gene resulting from depletion of SRA/SRAP could be confirmed. We conclude that the current model for SRAP function must be reevaluated; we suggest that SRAP may function in a different context to stabilize specific intermolecular interactions in the nucleus. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1766 / 1785
页数:20
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