Functional amyloids as molecular switches: emerging roles in diverse signalling pathways

Across all domains of life, functional amyloid fibrils serve structural, storage and signalling functions. In signalling pathways, assembly into the amyloid state constitutes a rapid and cooperative molecular switch that can reorganise protein function, promote multivalent interactions, and amplify downstream responses through templated self-propagation. Advances in the understanding of functional amyloids as regulators of signalling highlight their tailored structural properties and biological consequences. The nucleation-dependent polymerisation of amyloid enables sensitive control over activation thresholds, while the repetitive fibrillar architecture concentrates functional domains to enhance avidity and cooperativity. Controlled mechanisms for assembly, compartmentalisation and reversibility prevent inappropriate persistence or activity. These features underpin diverse signalling systems, including the RIPK1:RIPK3 necrosome in mammalian necroptosis, fungal prion-based cell-death pathways and prion-like regulatory systems in yeast and metazoans that modulate translation, development and cellular memory. Functional amyloids represent a versatile and evolutionarily conserved mechanism for molecular signalling and offer opportunities for the design of programmable amyloid-based switches with potential applications in therapeutics and synthetic biology.