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bioRxiv · 10.1101/2025.03.28.646059

Investigating the role of conformational heterogeneity in FUS-RRM fibrillation

Aazmi, O.·Aswale, A. R.·Saju, L.·Chugh, J.
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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. HighlightsO_LIFUS-RRM displays conformational heterogeneity in its folded monomeric state. C_LIO_LIA decrease in pH perturbs the conformational heterogeneity of the monomeric state. C_LIO_LIA lower pH condition accelerates the aggregation rate and also leads to a different fibril state. C_LIO_LIThe conformational heterogeneity provides a wider target search space for potential lead compounds in structure-based drug discovery. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/646059v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@ae0dacorg.highwire.dtl.DTLVardef@103c8caorg.highwire.dtl.DTLVardef@1736825org.highwire.dtl.DTLVardef@1ba6c72_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

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Aazmi, O., Aswale, A. R., Saju, L., Chugh, J.. 2025-04-02. Investigating the role of conformational heterogeneity in FUS-RRM fibrillation. https://doi.org/10.1101/2025.03.28.646059

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