Extreme disorder in an ultra-high-affinity protein complex

By Alessandro Borgia, Madeleine B. Borgia, Katrine Bugge, V. Kissling, Pétur O. Heidarsson, Catarina B. Fernandes, A. Sottini, Andrea Soranno, Karin J. Buholzer, D. Nettels and 3 more. 2018

588 citations recorded by the source corpus.

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding (2018, background): “While the majority of known disordered binding regions lose their flexibility upon interaction (with the exception of fuzzy complexes (6,7)), an order-to-disorder transition is the key for the function of another group of proteins.”
Distinct Structures and Dynamics of Chromatosomes with Different Human Linker Histone Isoforms (2020, background): “Chromatosomes were purified from extra ProTa by sizeexclusion chromatography (SEC) using Superose 6 10 300 GL column (GE Healthcare) preequilibrated with the same buffer.”
Analyzing Protein Disorder with IUPred2A (2020, background): “However, some IDRs retain a significant amount of flexibility even in the bound form, forming fuzzy complexes (Borgia et al., 2018; Miskei, Antal, & Fuxreiter, 2017).”
Intrinsically Disordered Proteins and Their “Mysterious” (Meta)Physics (2019, background): “Formation of such extremely disordered complexes with ultrahigh affinity was described for oppositely charged proteins, and was proposed to rely on long-range electrostatic attraction between the charge-rich regions of the polypeptide chains, instead of being dependent on some structurally defined b”