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Atomic Structures of Segments from TDP-43 LCD and insight into Reversible and Pathogenic Aggregation
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May 21 2018
Source: Nat Struct Mol Biol. 25(6):463-471
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Alternative Title:Nat Struct Mol Biol
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Description: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.
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Pubmed ID:29786080
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Pubmed Central ID:PMC5990464
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Funding:R01 AG029430/NIA NIH HHS/National Institute on Aging/United States ; P41 GM103403/NIGMS NIH HHS/National Institute of General Medical Sciences/United States ; RF1 AG054022/NIA NIH HHS/National Institute on Aging/United States ; S10 OD021527/ODCDC CDC HHS/Office of the Director/United States ; Howard Hughes Medical Institute/United States ; ... More +
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