The fate of mRNA once transcribed, spliced and transported to the cytoplasm is determined by the intricate interplay between RNA binding proteins (RBPs) and microRNAs (miRNAS) that interact with regulatory elements on mRNA. T-cell intracellular antigen-1 (TIA-1) is DNA/RNA binding protein involved in transcriptional and post-transcriptional regulation of eukaryotic gene expression, particularly under conditions of stress. Cellular stress results in the formation of stress granules, which are cytoplasmic foci in which mRNA can be held, protected from degradation, until the stress has passed. TIA-1 first binds A/U-rich elements in 3’UTR regions of mRNAs, and then escorts the translationally stalled mRNA, where they remain repressed until the stress granule is disassembled.

TIA-1 possesses three RNA recognition motifs RRM1, RRM2, RRM3 and a Q-rich domain. Among the domains, RRM2 is the major RNA recognition domain for U and A/U-rich sequences.  We have recently determined that RRM3 confers additional sequence specificity for a novel C-rich RNA motif [1], as shown by SPR experiments in our lab. This study aims to determine the detailed molecular structural basis of this specificity of RRM3 to C- rich sequences (using both SAXS and X-ray crystallography). This will elucidate the role of RRM3 in regulating TIA-1 binding to C-rich motifs that are numerous at the 5’ TOPs (5’ Terminal Oligopyrimidine Tracts) of mRNAs whose translation is repressed under stress conditions.

1.         Cruz-Gallardo, I., et al., The binding of TIA-1 to RNA C-rich sequences is driven by its C-terminal RRM domain. RNA Biol, 2014. 11(6).