Phe-Gly motifs drive fibrillization of TDP-43’s prion-like domain condensates
Open Access
- 28 April 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 19 (4), e3001198
- https://doi.org/10.1371/journal.pbio.3001198
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.Funding Information
- “la Caixa” Foundation (LCF/BQ/PR19/11700003)
- National Science Foundation (MCB1412253)
- AriSLA (PathensTDP)
- Ministerio de Economía, Industria y Competitividad, Gobierno de España (SAF2016-76678-C2-2- R)
This publication has 46 references indexed in Scilit:
- Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43Nature Structural & Molecular Biology, 2013
- Molecular Structure of β-Amyloid Fibrils in Alzheimer’s Disease Brain TissueCell, 2013
- Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic InclusionOnline Journal of Public Health Informatics, 2013
- Signals from the lysosome: a control centre for cellular clearance and energy metabolismNature Reviews Molecular Cell Biology, 2013
- Sequence correction of random coil chemical shifts: correlation between neighbor correction factors and changes in the Ramachandran distributionJournal of Biomolecular NMR, 2011
- Random coil chemical shift for intrinsically disordered proteins: effects of temperature and pHJournal of Biomolecular NMR, 2011
- Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral SclerosisScience, 2006
- Chemical Physics Letters, 2001
- Fluorescence anisotropy: Rapid, quantitative assay for protein-DNA and protein-protein interactionMethods in Enzymology, 1996
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995