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Title | Cryo-EM structures of four polymorphic TDP-43 amyloid cores. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 26, Issue 7, Page 619-627, Year 2019 |
Publish date | Jun 24, 2019 |
![]() | Qin Cao / David R Boyer / Michael R Sawaya / Peng Ge / David S Eisenberg / ![]() |
PubMed Abstract | 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 ...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 pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology. |
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Methods | EM (helical sym.) |
Resolution | 3.3 - 3.8 Å |
Structure data | EMDB-0334, PDB-6n3c: EMDB-9339, PDB-6n37: |
Source |
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![]() | PROTEIN FIBRIL / Amyloid / TDP43 / ALS / FTLD-TDP / dna binding protein |