Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of 'quasi-ordered' states

Elife. 2019 Oct 1;8:e50259. doi: 10.7554/eLife.50259.


Small heat shock proteins (sHSPs) are nature's 'first responders' to cellular stress, interacting with affected proteins to prevent their aggregation. Little is known about sHSP structure beyond its structured α-crystallin domain (ACD), which is flanked by disordered regions. In the human sHSP HSPB1, the disordered N-terminal region (NTR) represents nearly 50% of the sequence. Here, we present a hybrid approach involving NMR, hydrogen-deuterium exchange mass spectrometry, and modeling to provide the first residue-level characterization of the NTR. The results support a model in which multiple grooves on the ACD interact with specific NTR regions, creating an ensemble of 'quasi-ordered' NTR states that can give rise to the known heterogeneity and plasticity of HSPB1. Phosphorylation-dependent interactions inform a mechanism by which HSPB1 is activated under stress conditions. Additionally, we examine the effects of disease-associated NTR mutations on HSPB1 structure and dynamics, leveraging our emerging structural insights.

Keywords: HDXMS; HSPB1; NMR; intrinsically disordered protein; molecular biophysics; none; small heat shock protein; structural biology.

Publication types

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

MeSH terms

  • Amino Acid Sequence / genetics
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins, Small / genetics*
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Chaperones / genetics*
  • Protein Aggregates / genetics*
  • Protein Conformation
  • Protein Interaction Domains and Motifs / genetics*
  • Protein Multimerization / genetics
  • Scattering, Small Angle


  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Heat-Shock Proteins, Small
  • Molecular Chaperones
  • Protein Aggregates