TDP-43 controls RNA structure through high affinity lattice interactions.

Area of Science:

• Molecular Biology
• Neuroscience
• RNA Biology

Background:

• TDP-43 is an RNA binding protein linked to neurodegenerative diseases.
• TDP-43 preferentially binds to GU-rich sequences in human RNA.

Purpose of the Study:

• To elucidate the binding mechanism and specificity of TDP-43 to RNA.
• To investigate the interplay between TDP-43 binding and RNA structure formation.

Main Methods:

• Biophysical characterization of TDP-43-RNA interactions.
• All-atom molecular modeling.
• Analysis of RNA folding and protein binding kinetics.

Main Results:

• TDP-43 exhibits exceptionally high affinity and specificity for GU-rich RNA sequences.
• TDP-43 binding inhibits the formation of the pUG RNA quadruplex fold.
• TDP-43 recognizes RNA as a 1D lattice, with overlapping binding sites enhancing initial capture.
• RNA-facilitated protein-protein interactions modulate binding kinetics.

Conclusions:

• TDP-43's high-affinity RNA binding is mediated by a unique 1D lattice mechanism.
• The interplay between RNA folding and TDP-43 recognition is crucial and potentially relevant to neurodegenerative disease pathogenesis.