Distinct Roles of the N-terminal-binding Domain and the C-terminal-solubilizing Domain of α-Synuclein, a Molecular Chaperone

Abstract

␣-Synuclein, an acidic neuronal protein of 140 amino acids, is extremely heat-resistant and is natively unfolded. Recent studies have demonstrated that ␣-synuclein has chaperone activity both in vitro and in vivo, and that this activity is lost upon removing its C-terminal acidic tail. However, the detailed mechanism of the chaperone action of ␣-synuclein remains unknown. In this study, we investigated the molecular mechanism of the chaperone action of ␣-synuclein by analyzing the roles of its N-terminal and C-terminal domains. The N-terminal domain (residues 1-95) was found to bind to substrate proteins to form high molecular weight complexes, whereas the C-terminal acidic tail (residues 96 -140) appears to be primarily involved in solubilizing the high molecular weight complexes. Because the substrate-binding domain and the solubilizing domain for chaperone function are well separated in ␣-synuclein, the N-terminal-binding domain can be substituted by other proteins or peptides. Interestingly, the resultant engineered chaperone proteins appeared to display differential efficiency and specificity in terms of the chaperone function, which depended upon the nature of the binding domain. This finding implies that the C-terminal acidic tail of ␣-synuclein can be fused with other proteins or peptides to engineer synthetic chaperones for specific purposes.

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…These include many proteins associated with axonal transport (tau, dynactins, dynamins, dynein 1, filamins, GFAP, cofilins, microtubule‐associated proteins MAP1A & B, and neurofilament chains NFL, NFM, & NFH), neurotransmission (band 4.1‐like proteins, β‐SNAB, synapsins, synemin, and syntaxins), other neuronal processes (amine oxidase B, contactin 1, excitatory AA transporter 2, Na+/K+ transporter ATPase α2, tenascin receptor), redox control (peroxiredoxin 1, carbonyl reductase, and Mu‐class GSTs), signal transduction (14‐3‐3 proteins, elongation factor 1α, G α, β proteins, 6‐phosphofructokinase C), and proteostasis (heat‐shock proteins, MAP1 complex, peptidyl‐prolyl isomerase, sequestosome‐1, UBA‐1, polyubiquitin B, ubiquitin C‐terminal hydroxylase, vinculin). In contrast to those AD‐associated increases, α and β synucleins, characteristic of Parkinson inclusions (Park et al ., 2002), were depleted in tau‐ and Aβ‐IP aggregates derived from AD hippocampus.…”

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

“…Eliezer et al [23] had showed that the removal of the C-terminal acidic tail of α-Syn abolished its chaperone activity. In contrast, some reports indicate that the C-terminal acidic tail is indeed necessary but not sufficient for the chaperone function of α-Syn [28,29]. In normal physiological conditions, α-Syn exists in monomeric form and is recognized and cleared via the ubiquitin-proteasome system (UPS) and chaperone-mediated autophagy (CMA) pathways [39] (Figure 2).…”

“…It consists of an acidic domain rich in proline residues (residues 125-140) that seems critical for the chaperone-like activity of α-Syn [27], as demonstrated by deletion mutants of the C-terminal region in which the α-Syn chaperone activity is lost [27][28][29]. In contrast to the amphipathic N-terminal and hydrophobic NAC regions, which are highly conserved between species, the C-terminal region is variable in size and in sequence [28][29][30][31]. This region is also organized in random structure in most conditions and contains several phosphorylation sites: Ser129, Tyr125, Tyr133, and Tyr136 [32] (Figure 1).…”

Amyloid Polymorphism of α-Synuclein Induced by Active Firefly Luciferase

“…14 The protein has three distinctive segments in its primary structure including amphipathic N-terminal region (residues 1-60), central hydrophobic region (residues 61-95), and highly acidic C-terminal region (residues 96-140), which are demonstrated to be responsible for membrane interaction, protein aggregation, and multiple ligand interactions, respectively. [15][16][17][18][19][20][21][22][23][24][25] Various -synuclein interactive molecules have been reported to either inhibit or enhance the fibrillation of -synuclein. For instance, the fibril formation was accelerated by metal ions such as manganese, copper, iron, zinc, and aluminum, which altered the conformation of -synuclein.…”