Extreme diversity of 12 cations in folding ALS-linked hSOD1 unveils novel hSOD1-dependent mechanisms for Fe²⁺/Cu²⁺-induced cytotoxicity.

ABSTRACT: 153-Residue copper-zinc superoxide dismutase 1 (hSOD1) is the first gene whose mutation was linked to FALS. To date, > 180 ALS-causing mutations have been identified within hSOD1, yet the underlying mechanism still remains mysterious. Mature hSOD1 is exceptionally stable constrained by a disulfide bridge to adopt a Greek-key β-barrel fold that accommodates copper/zinc cofactors. Conversely, nascent hSOD1 is unfolded and susceptible to aggregation and amyloid formation, requiring Zn²⁺ to initiate folding to a coexistence of folded and unfolded states. Recent studies demonstrate mutations that disrupt Zn²⁺-binding correlate with their ability to form toxic aggregates. Therefore, to decode the role of cations in hSOD1 folding provides not only mechanistic insights, but m

SUBMITTER: Lim L 

PROVIDER: S-EPMC10645853 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature