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. 2021 Mar 12;12:1620. doi: 10.1038/s41467-021-21912-y

Fig. 4. Disease-related point mutations and phosphorylation sites mapped on the structure of one subunit of fibrils formed from the wild-type, non-phosphorylated TDP-43 LCD.

Fig. 4

a Mutations that are compatible with this structure are labeled in blue. The remaining mutations (labeled in red) are not compatible with the structure determined for wild-type protein fibrils due to steric clashes within tightly packed segments of the protein (S292N, M311V, S332N, G348C/V, S379P, A382P/T, S393L), introduction of charges into the dehydrated fibril interior (N378D, N390D), or both (G335D, G348R, G376D, G384R). P363 mutation would likely interfere with the formation of a turn observed in the fibril structure for the wild-type protein. Given that the 295–299 segment is relatively flexible in the present structure, the compatibility of A315E substitution (labeled in purple) with this structure is difficult to assess. b Phosphorylation sites exposed on the surface and those buried inside the structure determined for wild-type TDP-43 LCD fibrils are labeled in blue and red, respectively. Phosphorylation of exposed S410 would require only very small structural rearrangement of the backbone of C-terminal residues.