Molecular Horizons Seminar: Professor Nils G. Walter

At least 75% of the human genome is transcribed into RNA, but the vast majority of these transcripts do not code for proteins but rather for ‘non-coding’ RNAs (ncRNAs), many of which remain uncharacterized in terms of their structure and function. Currently, more than 80,000 unique ncRNAs have been identified in human cells, suggesting that for a long time we have underestimated the intricacies involved in human genome maintenance, processing, and regulation by neglecting this far-reaching ‘RNA World. Single molecule fluorescence resonance energy transfer (smFRET) allows us to measure dynamic distances in the underlying regulatory RNA:protein complexes at the 2-8 nm scale, whereas complementary super-resolution localization techniques access diffusive movements in the 10 nm and longer range.

Encapsulating the power of these advances, we have combined single-molecule and biochemical approaches to show that a central, adaptable RNA helix in the widespread manganese-sensing riboswitch functions analogous to a molecular fulcrum to integrate disparate signals for finely balanced bacterial gene expression control. We also have developed approaches for the single molecule tracking of fluorescently labeled proteins and RNAs forming nanodomains within biomolecular condensates, thus probing the liquid-liquid phase separation and fibrilization involved in human pathologies, using the RNA-binding model protein Fused-in-Sarcoma (FUS).