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Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

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 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.

journal_name

Nat Struct Mol Biol

journal_title

Nature structural & molecular biology

authors

Guenther EL,Cao Q,Trinh H,Lu J,Sawaya MR,Cascio D,Boyer DR,Rodriguez JA,Hughes MP,Eisenberg DS

doi

10.1038/s41594-018-0064-2

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

463-471

issue

6

eissn

1545-9993

issn

1545-9985

pii

10.1038/s41594-018-0064-2

journal_volume

25

pub_type

杂志文章

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