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- Title
Phe-Gly motifs drive fibrillization of TDP-43's prion-like domain condensates.
- Authors
Pantoja-Uceda, David; Stuani, Cristiana; Laurents, Douglas V.; McDermott, Ann E.; Buratti, Emanuele; Mompeán, Miguel
- Abstract
Transactive response DNA-binding Protein of 43 kDa (TDP-43) assembles various aggregate forms, including biomolecular condensates or functional and pathological amyloids, with roles in disparate scenarios (e.g., muscle regeneration versus neurodegeneration). The link between condensates and fibrils remains unclear, just as the factors controlling conformational transitions within these aggregate species: Salt- or RNA-induced droplets may evolve into fibrils or remain in the droplet form, suggesting distinct end point species of different aggregation pathways. Using microscopy and NMR methods, we unexpectedly observed in vitro droplet formation in the absence of salts or RNAs and provided visual evidence for fibrillization at the droplet surface/solvent interface but not the droplet interior. Our NMR analyses unambiguously uncovered a distinct amyloid conformation in which Phe-Gly motifs are key elements of the reconstituted fibril form, suggesting a pivotal role for these residues in creating the fibril core. This contrasts the minor participation of Phe-Gly motifs in initiation of the droplet form. Our results point to an intrinsic (i.e., non-induced) aggregation pathway that may exist over a broad range of conditions and illustrate structural features that distinguishes between aggregate forms. The prion-like domain of TDP-43 assembles biomolecular condensates which mature into amyloid fibrils that accumulate at the condensate/solvent interface. In vitro reconstitution of these fibrils reveals an amyloid core stabilized by residues that are not necessarily essential to create the droplet form.
- Subjects
DNA-binding proteins; MAGNETIC resonance microscopy; MUSCLE regeneration; AMYLOID
- Publication
PLoS Biology, 2021, Vol 19, Issue 4, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3001198