Metal Binding to Tau Protein: Physiological and Pathological Relevance

The microtubule-associated protein tau is an intrinsically disordered protein that exhibits a remarkable diversity of functions, while its amyloid aggregation is the hallmark of tauopathies, including Alzheimer's disease. This perspective article discusses recent advances in understanding copper and zinc binding to tau, the nature of the metal binding sites, and its physiological and pathological relevance. First, an argument for a potential role of metal binding in the interactome and diverse functionality of tau is provided, since metal coordination occurs in regions of tau engaged in its interaction with key binding partners. Then, the role of metal binding to tau in modulating its structural dynamics and amyloid aggregation behavior is discussed, with an emphasis on a potential role of metal ions in the morphological diversity of tau fibrils. Finally, the interplay between metal binding and post-translational modifications (PTMs) of tau is examined in physiological and pathological contexts, discussing how PTMs may influence metal coordination and how metals may modulate PTM processing of tau. Overall, this perspective delineates the exciting future of bioinorganic research related to tau protein, underscoring the importance of investigating the role of metal ions in tau biology as functional modulators and/or drivers of pathological transitions, linking metal homeostasis to tau physiology and disease.