ArticleThe EMBO journal2021
A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.
Article in The EMBO journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 25 citations in OpenAlex.
- Bromodomain dimers: A case study of BRD4 and family-wide AlphaFold predictions.Structural dynamics (Melville, N.Y.) · 2026Article
- Review
- TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins.Nature cell biology · 2025Article
- Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in Charcot-Marie-Tooth type 2 neuropathies.Autophagy · 2025Article
- Article
- O-GlcNAc modification of HSP27 alters its protein interactions and promotes refolding of proteins through the BAG3/HSP70 co-chaperone.Protein science : a publication of the Protein Society · 2024Article
- Advances and challenges in modeling inherited peripheral neuropathies using iPSCs.Experimental & molecular medicine · 2024Review
- From Milliseconds to Minutes: Melittin Self-Assembly from Concerted Non-Equilibrium Pressure-Jump and Equilibrium Relaxation Nuclear Magnetic Resonance.The journal of physical chemistry letters · 2024Article
- HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface.International journal of molecular sciences · 2023Article
- O-GlcNAc Modification Alters the Chaperone Activity of HSP27 Charcot-Marie-Tooth Type 2 (CMT2) Variants in a Mutation-Selective Fashion.ACS chemical biology · 2023Article
- HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.Autophagy · 2023Article
- Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.Nature cell biology · 2023Article
- Heterogeneous Clinical Phenotypes of dHMN Caused by Mutation inBiomolecules · 2022Article
- Article
- The role of BAG3 in dilated cardiomyopathy and its association with Charcot-Marie-Tooth disease type 2.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2022Review
- Large Chaperone Complexes Through the Lens of Nuclear Magnetic Resonance Spectroscopy.Annual review of biophysics · 2022Review
- Insights Into the Role of Heat Shock Protein 27 in the Development of Neurodegeneration.Frontiers in molecular neuroscience · 2022Review
- Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases.Frontiers in molecular biosciences · 2022Review
- Finding the sweet spot for chaperone activity.Nature chemistry · 2021Article
- A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.The EMBO journal · 2021Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 4 countries.
Funding
Abstract
HSP27 is a human molecular chaperone that forms large, dynamic oligomers and functions in many aspects of cellular homeostasis. Mutations in HSP27 cause Charcot-Marie-Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A particularly severe form of CMT disease is triggered by the P182L mutation in the highly conserved IxI/V motif of the disordered C-terminal region, which interacts weakly with the structured core domain of HSP27. Here, we observed that the P182L mutation disrupts the chaperone activity and significantly increases the size of HSP27 oligomers formed in vivo, including in motor neurons differentiated from CMT patient-derived stem cells. Using NMR spectroscopy, we determined that the P182L mutation decreases the affinity of the HSP27 IxI/V motif for its own core domain, leaving this binding site more accessible for other IxI/V-containing proteins. We identified multiple IxI/V-bearing proteins that bind with higher affinity to the P182L variant due to the increased availability of the IxI/V-binding site. Our results provide a mechanistic basis for the impact of the P182L mutation on HSP27 and suggest that the IxI/V motif plays an important, regulatory role in modulating protein-protein interactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.