Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 25, Issue 6, Pages 463-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0064-2
Keywords
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Funding
- National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]
- NIH-ORIP HEI grant [S10OD021527]
- DOE Office of Science [DE-AC02-06CH11357]
- National Institutes of Health [NIH NIA AG029430, NIH NIA AG054022]
- Howard Hughes Medical Institute
- Janelia Research Campus visitor program
- UCLA
- NIH [1S10RR23057, 1U24GM116792]
- NSF [DBI-1338135]
- National Science Foundation Graduate Research Fellowship Program
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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 beta-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 beta-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.
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