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A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins

ABSTRACT: HSP27 is a molecular chaperone that forms large oligomers and functions in many aspects of homeostasis. Mutations in HSP27 cause Charcot-Marie-Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A 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 core domain. Here, we observed that the P182L mutation disrupts the chaperone activity and increases the size of HSP27 oligomers, 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 core domain, leaving this binding site more accessible for other IxI/V-containing proteins. We identified multiple 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.

SUBMITTER: Dr. T., Reid Alderson

PROVIDER: S-SCDT-EMBOJ-2019-103811 | biostudies-other |

REPOSITORIES: biostudies-other

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A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.

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