The cover image of the November 5 issue of Biophysical Journal highlights our research on the structural dynamics of the RNA recognition motif (RRM) domains of TAR DNA binding protein 43 (TDP-43). These domains are crucial for recognizing GU-rich RNA sequences, and their dysfunction is linked to neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia.

The central image illustrates the fine details of intermolecular interactions between TDP-43 RRMs and a 12-nucleotide GU-RNA strand in their native complex. On the right, the RRMs (shown as spheres) are depicted in complex with GU-rich RNA (with nucleotides as sticks), forming a compact and stable structure. On the left, we highlight the sequence-specific binding mechanisms: conserved phenylalanine residues engage in π-π stacking, and electrostatic interactions, such as salt-bridges, cation-π, and hydrogen bonds, further stabilize the complex.

The surrounding configurations in coral and gray depict the conformational diversity of TDP-43 RRMs in the absence of RNA. Two key features emerge in this RNA-free state: (i) the non-covalent interactions between RRM1 and RRM2 weaken, causing them to move apart; and (ii) intradomain conformational flexibility increases, with a tendency for RRM1 to undergo partial unfolding. This significant conformational shift may explain TDP-43's functional versatility and its potential role in pathological aggregation.

These findings deepen our understanding of RNA-protein interactions and their implications in cellular processes and disease mechanisms. Our visualization offers a detailed look at how GU-rich RNA binding influences the conformational ensemble of TDP-43 RRMs, promoting TDP-43’s cellular function and preventing misfolding.

For more information about our work, please visit https://jeetain.wixsite.com/mittal-lab.

— Busra Ozguney, Priyesh Mohanty, and Jeetain Mittal