Staufen-swapping motif is crucial for Staufen dimerization, structure, and Staufen-mediated mRNA decay.

Human Staufen1 (hStau1, UniProt O95793.2) is a double-strand RNA (dsRNA) binding protein that modulates gene expression via mRNA-dependent mechanisms such as Staufen-mediated mRNA decay (SMD). This modular protein is dynamic and binds to both messanger RNA (mRNA) targets and proteins. The Staufen-swapping motif (SSM) domain is reported to play a key role in hStau1 dimerization. Our data confirm that SSM deletion decreases hStau1 dimerization. This protein shows higher protein disorder in the absence of SSM. Thus, SSM plays not only a key role in hStau1 dimerization but also modulates its tertiary structure. Surprisingly, increased disorder upon SSM deletion does not affect affinity for mRNA targets or protein/RNA stoichiometry but SMD efficiency since SMD targets are upregulated upon SSM deletion. In conclusion, hStau1 dimerization via SSM affects the overall structure and dynamics of the protein required for efficient regulation of gene expression via SMD.