Fig. 2: Cryo-EM structure of heteromeric amyloid filaments of ANXA11 and TDP-43 from FTLD-TDP type C.

a, Cryo-EM reconstruction of the left-handed filaments of ANXA11 and TDP-43 from FTLD-TDP type C, shown parallel to the helical axis. b, Identification of TDP-43 and ANXA11 chains in the ordered filament fold. ANXA11 was identified by deriving a sequence motif directly from well-resolved amino acid side-chain densities in the cryo-EM reconstruction (see Methods). c, Cryo-EM reconstruction and atomic model of the filaments, shown for single TDP-43 and ANXA11 chains perpendicular to the helical axis. The green arrow indicates an isolated peptide consistent with TDP-43 residues N352–G357. Buried ordered solvent is indicated with red dots. d,e, Domain organization of TDP-43 (d) and ANXA11 (e). ANX, annexin repeat; N, nuclear localization signal; RRM, RNA-recognition motif. The black lines indicate the regions that form the filament fold. f,g, Amino acid sequence alignment of the secondary structure elements of the TDP-43 (f) and ANXA11 (g) chains. The arrows indicate β-strands. The sequences that form the interface between TDP-43 and ANXA11 are underlined. In panels a–c, the cryo-EM density for TDP-43 is in grey and ANXA11 is in yellow. In panels b,c,f,g, the TDP-43 glycine-rich (G284–G310 in magenta), hydrophobic (M311–S342 in white) and Q/N-rich (Q343–Q345 in green) regions are highlighted. ANXA11 is shown in orange.