Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

Abstract

The aggregates of α-synuclein (αS) are a major pathological hallmark of Parkinson’s disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the αS aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available experimental data, we examined plausible molecular structures of αS(20/30–110) fibrils for the first time by employing computational approaches. The optimized structure was used to investigate possible interactions with aggregation inhibitors. Our structural models characterize the essential properties of the five-layered fold of the αS fibril. The distribution of the β-strands and the topology of the five β-strands in the relatively stable models are in good agreement with experimental values. In particular, we find that the KTK(E/Q)GV repeat motifs significantly stabilize the αS fibrils. The charged residues within each repeat prefer exposure to the solvent in order to further stabilize the inter-layered interactions by salt-bridges. The organization of the repeat K58T59K60E61Q62V63 between the β2 and β3 layers significantly affects the stability of the non-amyloid-component (NAC) domain. The coupling between the NAC domain and the KTKEGV repeats indicates that both regions can be potential binding sites for inhibitor design. The distinct binding modes of chemical agents that alter αS aggregation highlight the potential of our models in inhibitor design.

Study of Molecular Mechanisms of α-Synuclein Assembly: Insight into a Cross-β Structure in the N-Termini of New α-Synuclein Fibrils

“… 12 Initial constructed models of self-assembled AS(30–95) octamers. Model C1 is an ssNMR structure observed by Rienstra group, 15 model C2 is predicted from the computational study of Xu et al, 13 and model C3 is predicted in this study.…”

“…We further examined the self-assembled structures of AS(30–95) based on the fivefold model that consists of residues 30–110. 13 In C2 model ( Figure 1 ), the residues 96–110 in the original fivefold model were removed.…”

“… Polymorphic structures of the self-assembled NAC domain (residues 61–95) in AS obtained from (A) Rienstra group, 15 (B) Xu et al, 13 and (C) Atsmon-Raz and Miller. 12 Initial constructed models of self-assembled AS(30–95) octamers.…”

Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations

“…We found that the average RMSD values in the three MD runs of the isolated tetramer system during 250-300 ns were respectively 0.34, 0.32, and 0.32 nm; with the addition of DA/NE, the values changed to 0.35, 0.69, and 0.41 nm. Previous computational studies also reported that αS 20/30-110 pentamer [70], αS 61-95 pentamer [71], and αS 29-98 decamer [72] could maintain the β-sheet structures and display a stable conformation during the MD simulations. The increased RMSD value of αS tetramers with DA/NE molecules compared to those without DA/NE molecules suggested that the binding of DA/NE molecules led to a decreased structural stability of αS tetramer.…”

Multi-Pronged Interactions Underlie Inhibition of α-Synuclein Aggregation by β-Synuclein

“…It can also adopt a partial helical structure in the presence of a membrane [25, 26]. The mechanism by which αS self-associates has been extensively investigated [27–37], yet effective therapeutic strategies that inhibit αS aggregation processes and prevent the progression of Parkinson’s disease do not exist to date. However, several small molecules that interact with αS and alter the aggregation process, including phthalocyanine tetrasulfonates [38], epigallocatechin gallate [39], N-(4-Fluorophenyl)benzenesulfonamide [40], curcumin [41], CLR01 [42], gallic acid [43], and nortriptyline [44] have been identified.…”