Recent cryo-EM structures redefine the functional amyloid landscape

Amyloids are traditionally associated with neurodegenerative and systemic diseases, yet it is now clear that they also perform essential physiological functions across kingdoms of life. Over the last decade, advances in cryogenic electron microscopy (cryo-EM) have enabled high-resolution structural characterization of functional amyloids, transforming our understanding of how the amyloid fold can be repurposed for biological activity. A landmark study in 2020 reported the cryo-EM structure of Orb2, a neuronal amyloid required for long-term memory persistence, establishing the first atomic view of a nuclear amyloid fibril. Subsequent structures of human RNA-binding proteins that form functional amyloids further expanded this paradigm. The structure of hnRNPDL-2 revealed how prion-like low-complexity domains can assemble into highly ordered, stable fibrils while keeping the necessary functionality for RNA metabolism. More recently, cryo-EM structures of the pigment-associated amyloid PMEL have provided insight into the molecular basis of melanosome biogenesis and pigmentation. In parallel, structural studies of bacterial functional amyloids, including the biofilm protein FapC, have uncovered architectures optimized for mechanical robustness and environmental resilience. Together, these pioneering studies reveal shared structural principles, alongside organism-specific adaptations that distinguish functional amyloids from their pathological counterparts.