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How do multidomain RNA-binding proteins achieve high-affinity and sequence-selective RNA recognition? In our new bioRxiv preprint, we combine solution NMR spectroscopy, protein engineering, docking and biophysical measurements to investigate the tandem RNA recognition motifs (RRMs) of the Drosophila master regulator Sex-lethal (Sxl).

We show that the two RRMs are not independent domains but are linked by transient interdomain interactions that generate a dynamic conformational ensemble. Surprisingly, perturbing this equilibrium in either direction weakens RNA binding: extending the interdomain linker reduces coupling between the RRMs, while a structure-guided interface mutant unexpectedly increases coupling. Despite their opposite effects on domain dynamics, both perturbations impair RNA recognition.

Our results demonstrate that RNA recognition by Sxl is governed not by a single structure, but by a finely balanced conformational ensemble whose dynamic properties are essential for high-affinity and sequence-selective RNA binding.