6N37

SegA-sym, conformation of TDP-43 low complexity domain segment A sym

Summary for 6N37

• Entry DOI: 10.2210/pdb6n37/pdb
• EMDB information: 9339
• Descriptor: TAR DNA-binding protein 43 (1 entity in total)
• Functional Keywords: amyloid, tdp43, als, ftld-tdp, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 10
• Total formula weight: 52077.97

Authors

Cao, Q.,Boyer, D.R.,Sawaya, M.R.,Eisenberg, D.S. (deposition date: 2018-11-14, release date: 2019-06-26, Last modification date: 2024-03-20)

Primary citation

Cao, Q.,Boyer, D.R.,Sawaya, M.R.,Ge, P.,Eisenberg, D.S.
Cryo-EM structures of four polymorphic TDP-43 amyloid cores.
Nat.Struct.Mol.Biol., 26:619-627, 2019

PubMed Abstract: The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.

PubMed: 31235914
DOI: 10.1038/s41594-019-0248-4

Experimental method

ELECTRON MICROSCOPY (3.8 Å)