NIH Research Festival
The generation of Œ±-synuclein (Œ±-syn) truncations from incomplete proteolysis plays a significant role in the pathogenesis of Parkinson‚Äôs disease. Here, we report fibril structures of full-length acetylated (Ac) protein (Ac1‚Äì140), two C-terminally truncated Œ±-syn (Ac1‚Äì122 and Ac1‚Äì103), and an N-terminally truncated Œ±-syn (41‚Äì140) solved by cryoelectron microscopy. For the C-terminal truncations, both proteins exhibited faster aggregation kinetics and Ac1‚Äì103 fibrils efficiently seeded the full-length protein, highlighting their importance in pathogenesis. The removal of C-terminal residues resulted in increased fibrillar twist, accompanied by modest conformational changes in a more compact amyloid core. For 41‚Äì140, a novel amyloid structure with two asymmetric protofilaments was found. While one protomer resembled the previously characterized bent Œ≤-arch kernel, comprised of residues E46‚ÄíK96, the other protomer is folded into an extended Œ≤-hairpin conformation with fewer residues (E61‚ÄíD98) that does not resemble other reported structures. In stark contrast to the C-terminal truncations, fibrillar 41‚Äì140 had little effect on full-length Œ±-syn aggregation and fibril propagation. Together, these results offer new insights into Œ±-syn fibril polymorphism and the interplay between full-length and its truncations.
Scientific Focus Area: Biomedical Engineering and Biophysics
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