PROTEIN STRUCTURE

Not just a LARK

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Science  08 Jun 2018:
Vol. 360, Issue 6393, pp. 1083-1084
DOI: 10.1126/science.360.6393.1083-e

Many proteins involved in neurodegenerative diseases contain low-complexity domains (LCDs) that frequently exhibit no secondary structure but are implicated in both functional reversible aggregation and pathological irreversible aggregation. Guenther et al. determined the structures of 10 peptide segments from the LCD domain of the RNA binding protein TDP-43. The LCD is implicated in the formation of stress granules, which disaggregate when stress is relieved, and of pathogenic amyloid fibrils. Six of the segments form structures characteristic of amyloid fibrils, whereas four form labile amyloid-like interactions, termed LARKs. Disease variants of TDP-43 convert the LARKs to irreversible aggregates. This raises the possibility that either mutagenesis or protein modifications such as phosphorylation may play a role in switching between functional and pathological aggregation.

Nat. Struct. Mol. Biol. 10.1038/s41594-018-0064-2 (2018).

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