Extended Data Fig. 10. Core peptide and CTD fragments don’t recapitulate brain-derived filament structure.

(a) Amino acid sequence alignment of the secondary structure (β-strands) of the CP ‘H-fold,’ brain-derived TDP-43 filaments, and recombinant TDP-43 structures with the TDP-43 LC domain and its peptides. PDB IDs are given for the TDP-43 structures. The percentage represents the ratio of β-strand composition to the total peptide length. (b) Comparison of structural motifs of ‘H-fold’ TDP43 CP with brain-derived 282–360 TDP-43 filaments from ALS with FTLD (PDB-7PY2)²³, entire 276–414 TDP43 LCD (PDB 7KwZ)⁶⁹, and short TDP43 LCD fragments 288–319 (PDB-6N3C), 311–360 (PDB-6N3A), 312–347 (PDB-6N37), 312–352 (PDB-6N3B)⁶⁸. (c) Comparison of surface representations of cryo-EM structures of TDP-43 core fibrils from brain-derived²³ and our work. Red arrows point to the grooves on the surfaces of both fibrils. Interestingly, we noted some structural similarities on the surface of the CP fibrils with the brain-derived TDP-43 core structures described by Arseni et al.²³. For example, a single prominent surface groove formed by the main chain of G282-Q286 and the side chain of Q286 in the brain-derived TDP-43 filaments is also present in our ‘H-fold’ CP structure.