Tryptophan self-assembly yields cytotoxic nanofibers containing amyloid-mimicking and cross-seeding competent conformers.

Abstract

Dietary consumption of Trp via protein-based foods is essential for the maintenance of crucial metabolic processes including the synthesis of proteins and several vital metabolites such as serotonin, melatonin, acetyl CoA, and NADP. However, the abnormal build-up of Trp is known to cause familial hypertryptophanemia and several brain-related medical complications. The molecular mechanism of the onset of such Trp-driven health issues is largely unknown. Here, we show that Trp, under the physiologically mimicked conditions of temperature and buffer, undergoes a concentration driven self-assembly process, yielding amyloid-mimicking nanofibers. Viable H-bonds, π-π interactions and hydrophobic contacts between optimally coordinated Trp molecules become important factors for the formation of a Trp nanoassembly that displays a hydrophobic exterior and a hydrophilic interior. Importantly, Trp nanofibers were found to possess high affinity for native proteins, and they act as cross-seeding competent conformers capable of nucleating amyloid formation in globular proteins including whey protein β-lactoglobulin and type II diabetes linked insulin hormone. Moreover, these amyloid mimicking Trp nanostructures showed toxic effects on neuroblastoma cells. Since the key symptoms in hypertryptophanemia such as behavioural defects and brain-damaging oxidative stress are also observed in amyloid related disorders, our findings on amyloid-like Trp-nanofibers may help in the mechanistic understanding of Trp-related complications and these findings are equally important for innovation in applied nanomaterials design and strategies.