5WIA

Crystal structure of the segment, GNNSYS, from the low complexity domain of TDP-43, residues 370-375

Summary for 5WIA

• Entry DOI: 10.2210/pdb5wia/pdb
• Descriptor: TAR DNA-binding protein 43 (2 entities in total)
• Functional Keywords: amyloid, tdp-43, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 640.60

Authors

Guenther, E.L.,Trinh, H.,Sawaya, M.R.,Eisenberg, D.S. (deposition date: 2017-07-18, release date: 2018-04-25, Last modification date: 2024-04-03)

Primary citation

Guenther, E.L.,Cao, Q.,Trinh, H.,Lu, J.,Sawaya, M.R.,Cascio, D.,Boyer, D.R.,Rodriguez, J.A.,Hughes, M.P.,Eisenberg, D.S.
Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.
Nat. Struct. Mol. Biol., 25:463-471, 2018

PubMed 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.

PubMed: 29786080
DOI: 10.1038/s41594-018-0064-2

Experimental method

X-RAY DIFFRACTION (1.002 Å)