Extreme disorder in an ultrahigh-affinity protein complex

Alessandro Borgia (), Madeleine B. Borgia, Katrine Bugge, Vera M. Kissling, Pétur O. Heidarsson, Catarina B. Fernandes, Andrea Sottini, Andrea Soranno, Karin J. Buholzer, Daniel Nettels, Birthe B. Kragelund (), Robert B. Best () and Benjamin Schuler ()
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Alessandro Borgia: University of Zurich
Madeleine B. Borgia: University of Zurich
Katrine Bugge: Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), University of Copenhagen
Vera M. Kissling: University of Zurich
Pétur O. Heidarsson: University of Zurich
Catarina B. Fernandes: Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), University of Copenhagen
Andrea Sottini: University of Zurich
Andrea Soranno: University of Zurich
Karin J. Buholzer: University of Zurich
Daniel Nettels: University of Zurich
Birthe B. Kragelund: Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), University of Copenhagen
Robert B. Best: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Benjamin Schuler: University of Zurich

Nature, 2018, vol. 555, issue 7694, 61-66

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/nature25762

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