Exploring the Impact of Physiological C-Terminal Truncation on α-Synuclein Conformations to Unveil Mechanisms Regulating Pathological Aggregation

Abstract

Emerging evidence suggests that physiological C-terminal truncation of α-synuclein (αS) plays a critical role in regulating liquid–liquid phase separation and promoting amyloid aggregation, processes implicated in neurodegenerative diseases such as Parkinson’s disease (PD). However, the molecular mechanisms through which C-terminal truncation influences αS conformation and modulates its aggregation remain poorly understood. In this study, we investigated the impact of C-terminal truncation on αS conformational dynamics by comparing full-length αS 1–140 with truncated αS 1–103 monomers using atomistic discrete molecular dynamics simulations. Our findings revealed that both αS 1–140 and αS 1–103 primarily adopted helical conformations around residues 7–32, while residues 36–95, located in the second half of the N-terminal and NAC domains, predominantly formed a dynamic β-sheet core. The C-terminus of αS 1–140 was largely unstructured and dynamically wrapped around the β-sheet core. While residues 1–95 exhibited similar secondary structure propensities in both αS 1–140 and αS 1–103, the dynamic capping by the C-terminus in αS 1–140 slightly enhanced β-sheet formation around residues 36–95. In contrast, key aggregation-driving regions (residues 2–9, 36–42, 45–57, and 68–78) were dynamically shielded by the C-terminus in αS 1–140, reducing their exposure and potentially preventing interpeptide interactions that drive aggregation. C-terminal truncation, on the other hand, increased the exposed surface area of these aggregation-prone regions, thereby enhancing interpeptide interactions, phase separation, and amyloid aggregation. Overall, our simulations provide valuable insights into the conformational effects of C-terminal truncation on αS and its role in promoting pathological aggregation.

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