Designed Mutations Alter the Binding Pathways of an Intrinsically Disordered Protein

Sci Rep. 2019 Apr 16;9(1):6172. doi: 10.1038/s41598-019-42717-6.

Abstract

Many cellular functions, including signaling and regulation, are carried out by intrinsically disordered proteins (IDPs) binding to their targets. Experimental and computational studies have now significantly advanced our understanding of these binding processes. In particular, IDPs that become structured upon binding typically follow a dock-and-coalesce mechanism, whereby the docking of one IDP segment initiates the process, followed by on-target coalescence of remaining IDP segments. Multiple dock-and-coalesce pathways may exist, but one may dominate, by relying on electrostatic attraction and molecular flexibility for fast docking and fast coalescing, respectively. Here we critically test this mechanistic understanding by designing mutations that alter the dominant pathway. This achievement marks an important step toward precisely manipulating IDP functions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Humans
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / genetics
  • Intrinsically Disordered Proteins / metabolism*
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Signal Transduction
  • Wiskott-Aldrich Syndrome Protein / chemistry
  • Wiskott-Aldrich Syndrome Protein / genetics
  • Wiskott-Aldrich Syndrome Protein / metabolism*
  • cdc42 GTP-Binding Protein / chemistry
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism*

Substances

  • Intrinsically Disordered Proteins
  • WAS protein, human
  • Wiskott-Aldrich Syndrome Protein
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein