TDP-43 controls RNA structure through high affinity lattice interactions

TDP-43 is an RNA binding protein implicated in neurodegenerative disease. TDP-43 binds to GU dinucleotide repeats, which are highly abundant sequences in human RNA. Here we show TDP-43 has one of the highest affinities and specificities measured for an RNA binding protein. Binding prevents formation of the pUG fold, an intramolecular quadruplex, and conversely pUG fold formation prevents TDP-43 binding. Slow pUG folding and a rapid on-rate enable TDP-43 to capture single-stranded RNA. The protein recognizes the RNA as a 1D lattice, in which overlapping binding sites produce efficient initial binding events that interfere with subsequent interactions. This effect is overcome by RNA facilitated protein-protein interactions, which serve to increase the on-rate of a second TDP-43 molecule, and an auto-inhibitory interaction that increases the off-rate. These data reveal how TDP-43 recognizes GU repeats and identify an interplay between RNA folding and protein recognition that may be relevant to human disease.