Disulfide Bond Shuffling Induces Molecular Crosstalk: Delayed Insulin Aggregation and Enhanced Neurotoxicity

Our study explores the novel concept of disulfide bond shuffling-provoked oligomer crosstalk in insulin. We demonstrate that this dynamic process not only modulates the aggregation kinetics of insulin but also significantly influences its cytotoxic potential. Through a combination of biophysical techniques and cellular assays, we elucidate the molecular mechanisms underlying this phenomenon. Our findings reveal that disulfide bond shuffling in insulin oligomers can lead to the formation of novel, metastable species. These species, in turn, engage in crosstalk with other oligomers, thereby delaying the overall aggregation process. Intriguingly, our data also suggest that these metastable oligomers exhibit enhanced cytotoxicity compared to their fully aggregated counterparts. This observation underscores the potential biological implications of disulfide bond shuffling in insulin and opens up new avenues for investigating the role of protein misfolding and aggregation in disease pathogenesis.