Fig. 1

TDP-43 structure and phosphorylation sites. A Schematic of TDP-43, showing the N-terminus region (purple) with a nuclear localising signal (NLS), the binding region (blue) with two RNA-recognition motifs (RRM1, RRM2), and the C-terminus region (orange) with a glycine-rich domain. B TDP-43 phosphorylation sites detected in post-mortem ALS and FTLD-TDP brain and spinal cord tissue, along with potential phosphorylation sites [11,12,13, 52, 75,76,77]. Sites are listed by amino acid (serine (S), threonine (T), or tyrosine (Y)) and coloured by their localisation (N-terminus, purple; binding region, blue; C-terminus, orange). C-F “front”, (G-J) “left side”, (K-N) “right side”, and (O-R) “back” view of TDP-43 (Q13148) structure as predicted by AlphaFold3 and visualised in PyMOL. TDP-43 is represented in cartoon (C,G,K,O) or surface (E,I,M,Q) form, with the N-terminus in purple, binding region in blue, and the C-terminus in orange. D,H,L,P TDP-43 cartoon coloured by predicted Local Distance Difference Test (pLDDT), which shows regions with very high (dark blue, pLDDT > 90), high (light blue, pLDDT = 70–90), low (yellow, pLDDT = 50–70), and very low (orange, pLDDT < 50) confidence in the predicted structure as calculated by AlphaFold3. F,J,N,R Electrostatic surface potential (ESP) was calculated using APBS Electrostatics Plugin in Pymol where regions coloured red indicates negative potential, while regions indicate neutral potential, and blue indicate positive potential