Autonomous aggregation suppression by acidic residues explains why chaperones favour basic residues

EMBO J. 2020 Jun 2;39(11):e102864. doi: 10.15252/embj.2019102864. Epub 2020 Apr 1.


Many chaperones favour binding to hydrophobic sequences that are flanked by basic residues while disfavouring acidic residues. However, the origin of this bias in protein quality control remains poorly understood. Here, we show that while acidic residues are the most efficient aggregation inhibitors, they are also less compatible with globular protein structure than basic amino acids. As a result, while acidic residues allow for chaperone-independent control of aggregation, their use is structurally limited. Conversely, we find that, while being more compatible with globular structure, basic residues are not sufficient to autonomously suppress protein aggregation. Using Hsp70, we show that chaperones with a bias towards basic residues are structurally adapted to prioritize aggregating sequences whose structural context forced the use of the less effective basic residues. The hypothesis that emerges from our analysis is that the bias of many chaperones for basic residues results from fundamental thermodynamic and kinetic constraints of globular structure. This also suggests the co-evolution of basic residues and chaperones allowed for an expansion of structural variety in the protein universe.

Keywords: Hsp70; aggregation; gatekeepers; protein folding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Escherichia coli Proteins* / chemistry
  • Escherichia coli Proteins* / metabolism
  • Escherichia coli* / chemistry
  • Escherichia coli* / metabolism
  • HSP70 Heat-Shock Proteins* / chemistry
  • HSP70 Heat-Shock Proteins* / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Protein Aggregates*


  • Escherichia coli Proteins
  • HSP70 Heat-Shock Proteins
  • Protein Aggregates