Abstract
The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson’s disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that—Unlike in Aβ(1–42) amyloids—only the central fragment (30–100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1–30 and 100–140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain—as well as the aforementioned individual fragments—adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein’s internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1–30 and 100–140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30–100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment.
Highlights
A-synuclein is strongly expressed in brain tissue [1], at the presynaptic termini [2], and in synaptic membranes [3]
Based on the analysis presented in this paper, we suggest that their tendency to generate a globular structure with a prominent hydrophobic core may preclude fibrillization
The structure of the amyloid form of ASyn (PDB ID: 2N0A) consists of 10 chains, where—Unlike other amyloids listed in PDB [10,11,12,13,14,48]—Only a portion of each chain adopts a fibrillar form (in contrast, the entire chains of Aβ (1–42) amyloids participate in the formation of a fibril
Summary
A-synuclein (referred to as ASyn in our work) is strongly expressed in brain tissue [1], at the presynaptic termini [2], and in synaptic membranes [3]. The first 25 residues of the N-terminal fragment are responsible for anchoring the protein in the lipid bilayer, whereas, residues 26–98 mediate affinity towards the membrane, depending on the composition of the membrane itself [6]. This affinity is likely related to the biological activity of ASyn, which, remains poorly understood (see References [7,8] for further information). The amyloid form of ASyn (PDB ID: 2N0A [9]) comprises a fibrillar central fragment (30–100), while the remaining N- and
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