Disordered region encodes α-crystallin chaperone activity toward lens client γD-crystallin

Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2213765120. doi: 10.1073/pnas.2213765120. Epub 2023 Jan 31.


Small heat-shock proteins (sHSPs) are a widely expressed family of ATP-independent molecular chaperones that are among the first responders to cellular stress. Mechanisms by which sHSPs delay aggregation of client proteins remain undefined. sHSPs have high intrinsic disorder content of up to ~60% and assemble into large, polydisperse homo- and hetero-oligomers, making them challenging structural and biochemical targets. Two sHSPs, HSPB4 and HSPB5, are present at millimolar concentrations in eye lens, where they are responsible for maintaining lens transparency over the lifetime of an organism. Together, HSPB4 and HSPB5 compose the hetero-oligomeric chaperone known as α-crystallin. To identify the determinants of sHSP function, we compared the effectiveness of HSPB4 and HSPB5 homo-oligomers and HSPB4/HSPB5 hetero-oligomers in delaying the aggregation of the lens protein γD-crystallin. In chimeric versions of HSPB4 and HSPB5, chaperone activity tracked with the identity of the 60-residue disordered N-terminal regions (NTR). A short 10-residue stretch in the middle of the NTR ("Critical sequence") contains three residues that are responsible for high HSPB5 chaperone activity toward γD-crystallin. These residues affect structure and dynamics throughout the NTR. Abundant interactions involving the NTR Critical sequence reveal it to be a hub for a network of interactions within oligomers. We propose a model whereby the NTR critical sequence influences local structure and NTR dynamics that modulate accessibility of the NTR, which in turn modulates chaperone activity.

Keywords: chaperones; intrinsic disorder; protein aggregation; small heat-shock proteins.

Publication types

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

MeSH terms

  • Heat-Shock Proteins, Small* / metabolism
  • Humans
  • Lens, Crystalline* / metabolism
  • Molecular Chaperones / metabolism
  • alpha-Crystallin B Chain / metabolism
  • alpha-Crystallins* / metabolism


  • alpha-Crystallins
  • Molecular Chaperones
  • Heat-Shock Proteins, Small
  • alpha-Crystallin B Chain