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

Jinge GuXiaoming ZhouLillian SutherlandMasato KatoKlaudia JaczynskaJosep RizoSteven L McKnight
Published in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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 that the α-helical conformation allows interaction with a lipid-like detergent and that exposure to lipids enhances the β-to-α conformational switch. We hypothesize that regulation of this oxidative switch will prove to be important to the control of localized translation within vertebrate cells. The experimental observations reported herein were heavily reliant on studies of 1,6-hexanediol, a chemical agent that selectively dissolves labile structures formed via the self-association of protein domains of low sequence complexity. This aliphatic alcohol is shown to exert its dissociative activity primarily via hydrogen-bonding interactions with carbonyl oxygen atoms of the polypeptide backbone. Such observations underscore the central importance of backbone-mediated protein:protein interactions that facilitate the self-association and phase separation of LCDs.
Keyphrases
  • hydrogen peroxide
  • molecular dynamics simulations
  • molecular dynamics
  • induced apoptosis
  • mass spectrometry
  • amino acid
  • cell cycle arrest