Fused in sarcoma (FUS) is an RNA-binding protein that participates in multiple layers of RNA processing, including transcriptional control, splicing, and microRNA biogenesis. FUS consists of an N-terminal low-complexity (LC) domain, RNA-recognition motif (RRM), a zinc finger (ZnF), and several arginine/glycine-rich (RGG) domains. The C terminal domains mediate nucleic acid binding, providing FUS with the ability to engage in diverse RNA- and DNA-dependent processes. Within this architecture, the RRM displays unique structural features. While the isolated RRM adopts a stable fold, experimental results showed that the RRM structure is modified in the presence of other domains, suggesting the effects of long-range interdomain interactions. The RRM also exhibits a propensity for irreversible unfolding and amyloid fibril formation. Such behavior has been implicated in the transition of FUS from liquid droplets to amyloid aggregations observed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite this importance, the molecular details of how neighboring domains regulate the RRM remain poorly understood. Here, we address this gap by performing atomistic molecular dynamics simulations with advanced sampling techniques to examine the interaction between the RRM and the adjacent RGG2 region. We find that these interactions enhance the structural integrity of the RRM, maintaining its secondary structure more effectively than when the domain is studied in isolation. By uncovering how domain-domain communication modulates RRM stability, this work offers new insights into the mechanisms by which FUS transitions from its normal physiological assemblies to pathogenic states associated with ALS and FTD.
Rahimi et al. (Sun,) studied this question.