Investigating the role of conformational heterogeneity in FUS-RRM fibrillation

Abstract The Fused in Sarcoma (FUS) protein, previously implicated in neurodegenerative diseases, contains N- and C-terminal LC-rich regions, a zinc finger motif flanked by two RG-rich regions, and a single RNA-recognition motif (RRM). FUS-RRM monomers undergo amyloid-like aggregation, however, the detailed molecular insights into the fibrillation process are yet to be deciphered. Here, we investigated the conformational heterogeneity of FUS-RRM using NMR relaxation-dispersion experiments. We observed that the monomer (M) exists in a dynamic exchange with an excited state (ES), which gets perturbed by altering the pH. Although the overall fold of the FUS-RRM remains unperturbed at the lower pH, aggregation kinetics increase. The data suggests a coupling of the conformational heterogeneity to aggregation kinetics wherein a perturbation to ES probably acts as a switch that controls the fibrillation process under physiological and stress conditions. These results add to the understanding of the fibrillation process, thereby paving the way for a better understanding of the role of FUS in neurodegenerative diseases. Highlights FUS-RRM displays conformational heterogeneity in its folded monomeric state. A decrease in pH perturbs the conformational heterogeneity of the monomeric state. A lower pH condition accelerates the aggregation rate and also leads to a different fibril state. The conformational heterogeneity provides a wider target search space for potential lead compounds in structure-based drug discovery. Abstract Figure Graphical Abstract