ArticleProceedings of the National Academy of Sciences of the United States of America2020
Release of a disordered domain enhances HspB1 chaperone activity toward tau.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- Microtubule Cytoskeleton Dysfunction in Chronic Pain: Mechanisms of Transport Failure and Emerging Therapeutic Targets.International journal of molecular sciences · 2026Review
- Beyond the structure-function paradigm: A comprehensive review of intrinsically disordered proteins.Biochemistry and biophysics reports · 2026Review
- Chaperone proteins protect against desmin fragment amyloid aggregation.Biophysical journal · 2026Article
- Article
- A new perspective on iron-dependent cell death: PRDX-1-mediated ferroptosis in tumor cells.Apoptosis : an international journal on programmed cell death · 2025Review
- Capturing the Conformational Heterogeneity of HSPB1 Chaperone Oligomers at Atomic Resolution.Journal of the American Chemical Society · 2025Article
- Article
- Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection.Science advances · 2024Article
- Single-Cell Transcriptional Profiling and Gene Regulatory Network Modeling in Tg2576 Mice Reveal Gender-Dependent Molecular Features Preceding Alzheimer-Like Pathologies.Molecular neurobiology · 2024Article
- Hspb1 protects against severe acute pancreatitis by attenuating apoptosis and ferroptosis via interacting with Anxa2 to restore the antioxidative activity of Prdx1.International journal of biological sciences · 2024Article
- DnaJs are enriched in tau regulators.International journal of biological macromolecules · 2023Article
- HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface.International journal of molecular sciences · 2023Article
- Upregulation of Hsp27 via further inhibition of histone H2A ubiquitination confers protection against myocardial ischemia/reperfusion injury by promoting glycolysis and enhancing mitochondrial function.Cell death discovery · 2023Article
- The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.Cell reports · 2023Article
- Site-Specific Glycation of Human Heat Shock Protein (Hsp27) Enhances Its Chaperone Activity.ACS chemical biology · 2023Article
- Review
- Disordered region encodes α-crystallin chaperone activity toward lens client γD-crystallin.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology.eLife · 2022Article
- Large Chaperone Complexes Through the Lens of Nuclear Magnetic Resonance Spectroscopy.Annual review of biophysics · 2022Review
- Exercise suppresses mouse systemic AApoAII amyloidosis through enhancement of the p38 MAPK signaling pathway.Disease models & mechanisms · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Small heat shock proteins (sHSPs) are a class of ATP-independent molecular chaperones that play vital roles in maintaining protein solubility and preventing aberrant protein aggregation. They form highly dynamic, polydisperse oligomeric ensembles and contain long intrinsically disordered regions. Experimental challenges posed by these properties have greatly impeded our understanding of sHSP structure and mechanism of action. Here we characterize interactions between the human sHSP HspB1 (Hsp27) and microtubule-associated protein tau, which is implicated in multiple dementias, including Alzheimer's disease. We show that tau binds both to a well-known binding groove within the structured alpha-crystallin domain (ACD) and to sites within the enigmatic, disordered N-terminal region (NTR) of HspB1. However, only interactions involving the NTR lead to productive chaperone activity, whereas ACD binding is uncorrelated with chaperone function. The tau-binding groove in the ACD also binds short hydrophobic regions within HspB1 itself, and HspB1 mutations that disrupt these intrinsic ACD-NTR interactions greatly enhance chaperone activity toward tau. This leads to a mechanism in which the release of the disordered NTR from a binding groove on the ACD enhances chaperone activity toward tau. The study advances understanding of the mechanisms by which sHSPs achieve their chaperone activity against amyloid-forming clients and how cells defend against pathological tau aggregation. Furthermore, the resulting mechanistic model points to ways in which sHSP chaperone activity may be increased, either by native factors within the cell or by therapeutic intervention.
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