Format

Send to

Choose Destination
J Mol Biol. 2019 Sep 6;431(19):3913-3919. doi: 10.1016/j.jmb.2019.07.001. Epub 2019 Jul 8.

Structural Insights into α-Synuclein Fibril Polymorphism: Effects of Parkinson's Disease-Related C-Terminal Truncations.

Author information

1
Laboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2
Laboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
3
Laboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jiansen.jiang@nih.gov.
4
Laboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: leej4@nhlbi.nih.gov.

Abstract

Lewy bodies, hallmarks of Parkinson's disease, contain C-terminally truncated (ΔC) α-synuclein (α-syn). Here, we report fibril structures of three N-terminally acetylated (Ac) α-syn constructs, Ac1-140, Ac1-122, and Ac1-103, solved by cryoelectron microscopy. Both ΔC-α-syn variants exhibited faster aggregation kinetics, and Ac1-103 fibrils efficiently seeded the full-length protein, highlighting their importance in pathogenesis. Interestingly, fibril helical twists increased upon the removal of C-terminal residues and can be propagated through cross-seeding. Compared to that of Ac1-140, increased electron densities were seen in the N-terminus of Ac1-103, whereas the C-terminus of Ac1-122 appeared more structured. In accord, the respective termini of ΔC-α-syn exhibited increased protease resistance. Despite similar amyloid core residues, distinctive features were seen for both Ac1-122 and Ac1-103. Particularly, Ac1-103 has the tightest packed core with an additional turn, likely attributable to conformational changes in the N-terminal region. These molecular differences offer insights into the effect of C-terminal truncations on α-syn fibril polymorphism.

KEYWORDS:

Raman spectroscopy; TEM; amyloid; cryoEM; thioflavin T

PMID:
31295458
PMCID:
PMC6733637
[Available on 2020-09-06]
DOI:
10.1016/j.jmb.2019.07.001

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center