Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

Significance The TDP43 RNA binding protein is frequently aggregated in the brain tissue of patients suffering from neurodegenerative diseases. Human genetic studies of patients suffering from ALS have identified scores of missense mutations clustered within a localized region of the TDP43 protein. This region is of low sequence complexity and has been thought to exist in a state of structural disorder under conditions of proper TDP43 function. The present study gives evidence that the low complexity domain of TDP43 self-associates into a specific structural conformation that may be important to its normal biological function. Unlike prototypic low complexity domains, that of TDP43 is methionine-rich. Evidence is presented suggestive of the utility of these methionine residues in oxidation-mediated regulation of TDP43 function.