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Title | Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 25, Issue 6, Page 463-471, Year 2018 |
Publish date | May 21, 2018 |
Authors | Elizabeth L Guenther / Qin Cao / Hamilton Trinh / Jiahui Lu / Michael R Sawaya / Duilio Cascio / David R Boyer / Jose A Rodriguez / Michael P Hughes / David S Eisenberg / |
PubMed Abstract | The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is ...The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation. |
External links | Nat Struct Mol Biol / PubMed:29786080 / PubMed Central |
Methods | EM (electron crystallography) / X-ray diffraction |
Resolution | 0.75 - 1.8 Å |
Structure data | EMDB-7466, PDB-6cf4: EMDB-7467: SWGMMGMLASQ segment from the low complexity domain of TDP-43, residues 333-343 EMDB-8857, PDB-5wkb: PDB-5whn: PDB-5whp: PDB-5wia: PDB-5wiq: PDB-5wkd: PDB-6cb9: PDB-6cew: |
Chemicals | ChemComp-HOH: |
Source |
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Keywords | PROTEIN FIBRIL / Amyloid / LARKS / TDP-43 / low complexity domain / Steric-zipper / Reversible aggregation / steric zipper |