Conformational landscapes of Huntingtin's polyQ domain and variations in its aggregate morphology

Abstract

Huntingtons disease (HD) is a fatal neurodegenerative disorder resulting from an abnormal expansion of polyglutamine (polyQ) repeats in the N terminus of the Huntingtin protein. When the polyQ tract surpasses 35 repeats, the mutated protein undergoes misfolding, culminating in the formation of intracellular aggregates. Research in mouse models suggests that HD pathogenesis involves the aggregation of N-terminal fragments of the Huntingtin protein (htt). These early oligomeric assemblies of htt, exhibiting diverse characteristics during aggregation, are implicated as potential toxic entities in HD. However, a consensus on their specific structures remains elusive. Understanding the heterogeneous nature of htt oligomers provides crucial insights into disease mechanisms, emphasizing the need to identify various oligomeric conformations as potential therapeutic targets. Employing coarse-grained molecular dynamics, our study aims to elucidate the mechanisms governing the aggregation process and resultant aggregate architectures of htt. The polyQ tract within htt is flanked by two regions: an N-terminal domain (N17) and a short C-terminal proline-rich segment. We conducted self-assembly simulations involving five distinct N17 + polyQ systems with polyQ lengths ranging from 7 to 45, utilizing the ProMPT force field. Prolongation of the polyQ domain correlates with an increase in {beta}-sheet-rich structures. Longer polyQ lengths favor intra-molecular {beta}-sheets over inter-molecular interactions due to the folding of the elongated polyQ domain into hairpin-rich conformations. Importantly, variations in polyQ length significantly influence resulting oligomeric structures. Shorter polyQ domains lead to N17 domain aggregation, forming a hydrophobic core, while longer polyQ lengths introduce a competition between N17 hydrophobic interactions and polyQ polar interactions, resulting in densely packed polyQ cores with outwardly distributed N17 domains. Additionally, at extended polyQ lengths, we observe distinct oligomeric conformations with varying degrees of N17 bundling. These findings can help explain the toxic gain-of function that htt with expanded polyQ acquires. Author summaryOur study delves into Huntingtons disease (HD), a devastating neurodegenerative disorder triggered by abnormal expansions of polyglutamine repeats in the Huntingtin protein. When these repeats exceed a critical threshold, the protein misfolds, leading to the formation of harmful intracellular aggregates. Using computational techniques, we explored the intricate process by which these aggregates form and examined their complex structures. Our findings shed light on the diverse nature of the protein fragments involved in HD pathology, emphasizing the importance of identifying various structural forms as potential targets for therapeutic intervention. We observed that changes in the length of the polyglutamine tract significantly impact the resulting aggregate structures, revealing insights into the disease mechanism. Specifically, we found that an expansion of the polyglutamine domain leads to distinct aggregate morphologies. In addition, the way the first 17 amino acids of these protein fragments pack against each other in the aggregates depends on the length of the polyglutamine repeats. By uncovering these structural intricacies, our study contributes to a deeper understanding of HD and may pave the way for the development of targeted treatments aimed at disrupting or preventing the formation of toxic protein aggregates.