Extreme disorder in an ultrahigh-affinity protein complex

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

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Histones / chemistry*
  • Histones / metabolism*
  • Humans
  • Intrinsically Disordered Proteins / chemistry*
  • Intrinsically Disordered Proteins / metabolism*
  • Protein Binding
  • Protein Precursors / chemistry*
  • Protein Precursors / metabolism*
  • Static Electricity
  • Thymosin / analogs & derivatives*
  • Thymosin / chemistry
  • Thymosin / metabolism

Substances

  • Histones
  • Intrinsically Disordered Proteins
  • Protein Precursors
  • prothymosin alpha
  • Thymosin