A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins
Open Access
- 1 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 40 (8), e103811
- https://doi.org/10.15252/embj.2019103811
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.Keywords
Funding Information
- Biotechnology and Biological Sciences Research Council (BB/J014346/1, BB/J018082/1)
- Engineering and Physical Sciences Research Council (EP/J01835X/1)
- Association Belge contre les Maladies Neuro-Musculaires
- National Institute of Diabetes and Digestive and Kidney Diseases
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