Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch.

ABSTRACT: An evolutionarily conserved region of the TDP-43 low-complexity domain (LCD) twenty residues in length can adopt either an α-helical or β-strand conformation. When in the latter conformation, TDP-43 self-associates via the formation of a labile, cross-β structure. Self-association can be monitored via the formation of phase-separated protein droplets. Exposure of droplets to hydrogen peroxide leads to oxidation of conserved methionine residues distributed throughout the LCD. Oxidation disassembles the cross-β structure, thus eliminating both self-association and phase separation. Here, we demonstrate that this process reciprocally enables formation of α-helical structure in precisely the same region formerly functioning to facilitate β-strand-mediated self-association. We further observe t

SUBMITTER: Gu J 

PROVIDER: S-EPMC10576115 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature