Reversible amyloids encode biomolecular memory through hysteresis

Hysteresis — the dependence of a system’s state on its history — is functionally exploited in biology to achieve robustness and memory, for example in cell cycle commitment, ion channel gating, and enzyme regulation. Here we show that hysteresis naturally emerges in reversible amyloid formation, establishing a physicochemical basis for information storage at the molecular level. Using pH-induced reversible amyloid formation by pyruvate kinase M2 (PKM2) as a model, we demonstrate that hysteresis arises from the distinct pathways of aggregation and disaggregation: as with most amyloids, metastable intermediates are required for nucleation but bypassed during disassembly. In the PKM2 system the solubilities of intermediates and fibrils are affected differently by the protonation-dependent charge of the amyloid core. Mutations that alter this charge profile shift the hysteresis window in predictable ways, illustrating how the phenomenon can be rationally tuned. Our results provide a mechanistic framework for hysteresis in protein self-assembly and identify reversible amyloids as a new class of memory-encoding molecular systems.