Dissecting how ALS-associated D290V mutation enhances pathogenic aggregation of hnRNPA2286–291 peptides: Dynamics and conformational ensembles

Abstract

The aggregation of RNA binding proteins, including hnRNPA1/2, TDP-43 and FUS, is heavily implicated in causing or increasing disease risk for a series of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A recent experimental study demonstrated that an ALS-related D290V mutation in the low complexity domain (LCD) of hnRNPA2 can enhance the aggregation propensity of wild type (WT) hnRNPA2286–291 peptide. However, the underlying molecular mechanisms remain elusive. Herein, we investigated effects of D290V mutation on aggregation dynamics of hnRNPA2286–291 peptide and the conformational ensemble of hnRNPA2286–291 oligomers by performing all-atom molecular dynamic and replica-exchange molecular dynamic simulations. Our simulations demonstrate that D290V mutation greatly reduces the dynamics of hnRNPA2286–291 peptide and that D290V oligomers possess higher compactness and β-sheet content than WT, indicative of mutation-enhanced aggregation capability. Specifically, D290V mutation strengthens inter-peptide hydrophobic, main-chain hydrogen bonding and side-chain aromatic stacking interactions. Those interactions collectively lead to the enhancement of aggregation capability of hnRNPA2286–291 peptides. Overall, our study provides insights into the dynamics and thermodynamic mechanisms underlying D290V-induced disease-causing aggregation of hnRNPA2286–291, which could contribute to better understanding of the transitions from reversible condensates to irreversible pathogenic aggregates of hnRNPA2 LCD in ALS-related diseases.