Proteins that bind RNA often combine structured and unstructured regions, but how these domains cooperate has remained unclear. A new study from the Institute of Science Tokyo offers molecular-level detail on this process, focusing on the FUS protein, which plays roles in gene regulation and has been linked to neurodegenerative disease.
FUS contains a RanBP2-type zinc finger (ZnF) domain, known for recognizing specific RNA sequences, followed by intrinsically disordered regions (IDRs). Using molecular dynamics simulations with enhanced sampling, Akio Kitao and Soichiro Kijima examined how these domains interact with a short RNA strand carrying the GGU sequence. The work was published in the Journal of Chemical Information and Modeling.
The simulations identified two distinct binding modes. In one, the ZnF domain alone contacted the RNA but did so weakly. In the other, the ZnF and the IDR acted together, forming a complex nearly ten times more stable. “We observed that the structured ZnF domain recognizes specific RNA sequences, but on its own, it binds only weakly,” said Kitao. “Surprisingly, it was the disordered IDR which boosts this interaction.”
The IDR attached through charge-based interactions with RNA phosphate groups and distorted the RNA backbone, further stabilizing the complex. These non-sequence-specific contacts reduced the dissociation constant two-fold, strengthening overall affinity. “Our findings suggest that IDRs aren’t just passive linkers,” Kitao noted. “They actively contribute to the RNA-binding mechanism.”
Sequence analysis of other proteins with IDRs indicates that this cooperative binding strategy may extend beyond FUS, providing a framework for understanding how proteins achieve both specificity and flexibility in RNA recognition.
Publication Details
Kijima, Soichiro, and Akio Kitao. "RNA Binding Mechanism of the FUS Zinc Finger in Concert with Its Flanking Intrinsically Disordered Region." Journal of Chemical Information and Modeling (2025).
FUS contains a RanBP2-type zinc finger (ZnF) domain, known for recognizing specific RNA sequences, followed by intrinsically disordered regions (IDRs). Using molecular dynamics simulations with enhanced sampling, Akio Kitao and Soichiro Kijima examined how these domains interact with a short RNA strand carrying the GGU sequence. The work was published in the Journal of Chemical Information and Modeling.
The simulations identified two distinct binding modes. In one, the ZnF domain alone contacted the RNA but did so weakly. In the other, the ZnF and the IDR acted together, forming a complex nearly ten times more stable. “We observed that the structured ZnF domain recognizes specific RNA sequences, but on its own, it binds only weakly,” said Kitao. “Surprisingly, it was the disordered IDR which boosts this interaction.”
The IDR attached through charge-based interactions with RNA phosphate groups and distorted the RNA backbone, further stabilizing the complex. These non-sequence-specific contacts reduced the dissociation constant two-fold, strengthening overall affinity. “Our findings suggest that IDRs aren’t just passive linkers,” Kitao noted. “They actively contribute to the RNA-binding mechanism.”
Sequence analysis of other proteins with IDRs indicates that this cooperative binding strategy may extend beyond FUS, providing a framework for understanding how proteins achieve both specificity and flexibility in RNA recognition.
Publication Details
Kijima, Soichiro, and Akio Kitao. "RNA Binding Mechanism of the FUS Zinc Finger in Concert with Its Flanking Intrinsically Disordered Region." Journal of Chemical Information and Modeling (2025).