TDP-43 -helical structure tunes liquid-liquid phase separation and function Institutional Repository Document uri icon


  • AbstractLiquid-liquid phase separation (LLPS) is involved in the formation of membraneless organelles (MLOs) associated with RNA processing. Present in several MLOs, TDP-43 undergoes LLPS and is linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). While some disease variants of TDP-43 disrupt self-interaction and function, here we show that designed single mutations can enhance TDP-43 assembly and function via modulating helical structure. Using molecular simulation and NMR spectroscopy, we observe large structural changes in a dimeric TDP-43. Two conserved glycine residues (G335 and G338) are potent inhibitors of helical extension and helix-helix interaction, which are removed in part by variants including the ALS-associated G335D. Substitution to helix-enhancing alanine at either of these positions dramatically enhances phase separation in vitro and decreases fluidity of phase separated TDP-43 reporter compartments in cells. Furthermore, G335A increases TDP-43 splicing function in a mini-gene assay. Therefore, TDP-43 helical region serves as a short but uniquely tunable module that shows promise as for controlling assembly and function in cellular and synthetic biology applications of LLPS.

altmetric score

  • 11.2

author list (cited authors)

  • Conicella, A. E., Dignon, G. L., Zerze, G. H., Schmidt, H. B., DOrdine, A. M., Kim, Y. C., ... Fawzi, N. L.

citation count

  • 5

complete list of authors

  • Conicella, Alexander E||Dignon, Gregory L||Zerze, Gül H||Schmidt, Hermann Broder||D’Ordine, Alexandra M||Kim, Young C||Rohatgi, Rajat||Ayala, Yuna M||Mittal, Jeetain||Fawzi, Nicolas L

Book Title

  • bioRxiv

publication date

  • May 2019