Structure and topology of the non‐amyloid‐β component fragment of human α‐synuclein bound to micelles: Implications for the aggregation process

Abstract

Human a-synuclein is a small soluble protein abundantly expressed in neurons. It represents the principal constituent of Lewy bodies, the main neuropathological characteristic of Parkinson's disease. The fragment corresponding to the region 61-95 of the protein, originally termed NAC (non-amyloid-b component), has been found in amyloid plaques associated with Alzheimer's disease, and several reports suggest that this region represents the critical determinant of the fibrillation process of a-synuclein. To better understand the aggregation process of a-synuclein and the role exerted by the biological membranes, we studied the structure and the topology of the NAC region in the presence of SDS micelles, as membrane-mimetic environment. To overcome the low solubility of this fragment, we analyzed a recombinant polypeptide corresponding to the sequence 57-102 of a-synuclein, which includes some charged amino acids flanking the NAC region. Three distinct helices are present, separated by two flexible stretches. The first two helices are located closer to the micelle surface, whereas the last one seems to penetrate more deeply into the micelle. On the basis of the structural and topological results presented, a possible pathway for the aggregation process is suggested. The structural information described in this work may help to identify the appropriate target to reduce the formation of pathological a-synuclein aggregation.

Structural Properties of Fibril-forming Segments of α-Synuclein

“…33,34 Even though the structures of α-synuclein are known to be mostly disordered without definite secondary structures, the secondary structure profile obtained from our calculations suggest that the NAC region can be divided into roughly three helical-like segments. This result is qualitatively consistent with experiment 35 and computational prediction of nonnative sequence propensity. 36 It is found that the α-helix content slightly decreases as the temperature is raised while the turn increases.…”

“…Recently, Bisaglia et al studied the structure and topology of NAC peptide in the membrane-mimetic environment. 42 It is found that in the membrane-mimetic environment, NAC peptide forms characteristic three regions of helical conformation with C-terminal region less stable. The lowest energy structures were calculated from NOE-based distance restraints and the backbone dihedral angles were derived from chemical shifts.…”

Application of the Fuzzy Oil Drop Model Describes Amyloid as a Ribbonlike Micelle

“…A discussion of issues related to protein micelles-with a particular focus on the most common type of micellar structure, i.e., a membrane, as well as the role of detergents, can be found in [57]. The opinion "more and more secreted proteins have been found to have the potential to produce extracellular amyloid deposits in multiple organs" was expressed in [58,59].…”

“…Experimental studies concerning amyloidogenesis point to the special role of hydrophobic residues [55][56][57]. If interactions between residues forming the sequence do not promote the formation of a common, central hydrophobic core, a different type of ordering may take hold-one in which local peaks and troughs aggregate linearly.…”

The role of retromer in Parkinson's disease

“…The central region of the α-synuclein (61-95AA) comprises a domain which contains amino acids prone to self-aggregation and is called the Non-Amyloid beta Component (NAC) domain [189]. Structural evidence of recombinant NAC domain demonstrated that it may possess helical conformation that allows direct interaction with the micelle surface [193]. In contrast, the Carboxy terminal does not have an known secondary structure and overall, possesses a strong negative charge due to the strong prevalence of 27 aspartic and glutamic acid residues [191,194].…”