Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of 'quasi-ordered' states
- University of Washington, United States
Abstract
Small heat shock proteins (sHPSs) 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 a-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.
Data availability
NMR resonance assignments have been deposited in BMRB; accession number 27681.Data generated for this study are included in the manuscript and supporting figures and tables.Source data for HDXMS data included in Figures 7 and 9 and associated Supplemental Tables are provided as Excel spreadsheet.
Article and author information
Author details
Funding
National Eye Institute (R01 EY017370)
- Rachel E Klevit
National Institute of General Medical Sciences (R01 GM127579)
- Miklos Guttman
National Institute of General Medical Sciences (NIH T32 GM008268)
- Amanda F Clouser
- Hannah ER Baughman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Clouser et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of 'quasi-ordered' states
eLife 8:e50259.
https://doi.org/10.7554/eLife.50259
