Dataset Information

Cryo-EM structures of four polymorphic TDP-43 amyloid cores

ABSTRACT:

SUBMITTER: David R Boyer

PROVIDER: EMPIAR-10497 | biostudies-other |

REPOSITORIES: biostudies-other

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Publications

Cryo-EM structures of four polymorphic TDP-43 amyloid cores.

Cao Qin Q Boyer David R DR Sawaya Michael R MR Ge Peng P Eisenberg David S DS

Nature structural & molecular biology 20190624 7

The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the path ...[more]

PMID: 31235914

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Project description:BACKGROUND: Misfolding and self-assembly of Amyloid-? (A?) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic A? structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these A? species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of A? globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although A? globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated ?-structure in A? globulomers make them difficult to convert into other high-order A? aggregates and fibrils with dominant ?-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These A? globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled A? globulomers provide useful insights into structure, dynamics, and polymorphic nature of A? globulomers which are completely different from A? fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between A? globulomers and fibrils.

Dataset Information

Cryo-EM structures of four polymorphic TDP-43 amyloid cores

Publications

Cryo-EM structures of four polymorphic TDP-43 amyloid cores.

Similar Datasets

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