As(III)-induced protein aggregation: insights and emerging possibilities for As(III)-responsive proteins

Arsenic (As(III)), a toxic metalloid, binds strongly to cysteine thiols and induces protein misfolding and aggregation. Recent studies-mainly using Escherichia coli-have revealed how As(III)-induced aggregation occurs in cells and how this process can be exploited to design As(III)-responsive proteins. This mini-review highlights two strategies based on As(III)-triggered structural transitions. The quorum-sensing regulator LuxR undergoes As(III)-dependent aggregation that switches its transcriptional activity from ON to OFF, establishing the first aggregation-based whole-cell sensor and revealing an intracellular As(III) threshold required for switching. Inspired by this mechanism, the cysteine-free repressor BetI was rationally engineered to gain As(III) responsiveness through cysteine introduction, enabling As(III)-induced conformational activation. These findings demonstrate that As(III)-induced aggregation, once considered purely toxic, provides a foundation for developing proteins with controllable structural and functional switching.