The functions of proteins have traditionally been linked to their well-defined three-dimensional, folded structures. However, it is becoming increasingly clear that many proteins perform essential functions without being folded. A versatile approach for investigating the structure, dynamics, and function of such intrinsically disordered proteins (IDPs) is the integration of single-molecule FRET with other biophysical methods and molecular simulations. I will illustrate this approach in the context of an unexpected interaction mechanism: Two intrinsically disordered and highly charged human proteins, histone H1 and its nuclear chaperone prothymosin α, associate with picomolar affinity, but they fully retain their structural disorder, long-range flexibility, and highly dynamic character. We obtained a detailed model of this highly disordered protein complex, which is stabilized by the large opposite net charges of the two proteins and does not require interactions between defined binding sites or specific individual residues. This type of interaction has interesting consequences for kinetic mechanisms of binding and cellular regulation.
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