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Nature. 2018 Mar 1;555(7694):61-66. doi: 10.1038/nature25762. Epub 2018 Feb 21.

Extreme disorder in an ultrahigh-affinity protein complex.

Author information

1
Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.
2
Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark.
3
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
4
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.
5
Department of Physics, University of Zurich, 8057 Zurich, Switzerland.

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.

PMID:
29466338
PMCID:
PMC6264893
DOI:
10.1038/nature25762
[Indexed for MEDLINE]
Free PMC Article

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