Increased Monomerization of Mutant HSPB1 Leads to Protein Hyperactivity in Charcot-Marie-Tooth Neuropathy

Small heat shock proteins are molecular chaperones capable of maintaining denatured proteins in a folding-competent state. We have previously shown that missense mutations in the small heat shock protein HSPB1 (HSP27) cause distal hereditary motor neuropathy and axonal Charcot-Marie-Tooth disease. H...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-04, Vol.285 (17), p.12778-12786
Main Authors: Almeida-Souza, Leonardo, Goethals, Sofie, de Winter, Vicky, Dierick, Ines, Gallardo, Rodrigo, Van Durme, Joost, Irobi, Joy, Gettemans, Jan, Rousseau, Frederic, Schymkowitz, Joost, Timmerman, Vincent, Janssens, Sophie
Format: Article
Language:English
Subjects:
Cell Line
Chaperones/Heat Shock
Chaperones/Protein Folding
Chaperonopathy
Charcot-Marie-Tooth
Charcot-Marie-Tooth Disease - genetics
Charcot-Marie-Tooth Disease - metabolism
Diseases/Neurodegeneration
Female
Heat Shock Protein
Heat-Shock Proteins
Heat-Shock Response
HSP27
HSP27 Heat-Shock Proteins - genetics
HSP27 Heat-Shock Proteins - metabolism
Humans
Male
Molecular Bases of Disease
Molecular Chaperones
Mutation
Neurodegeneration
Protein Multimerization
Protein Structure and Folding
Protein/Folding
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Summary:Small heat shock proteins are molecular chaperones capable of maintaining denatured proteins in a folding-competent state. We have previously shown that missense mutations in the small heat shock protein HSPB1 (HSP27) cause distal hereditary motor neuropathy and axonal Charcot-Marie-Tooth disease. Here we investigated the biochemical consequences of HSPB1 mutations that are known to cause peripheral neuropathy. In contrast to other chaperonopathies, our results revealed that particular HSPB1 mutations presented higher chaperone activity compared with wild type. Hyperactivation of HSPB1 was accompanied by a change from its wild-type dimeric state to a monomer without dissociation of the 24-meric state. Purification of protein complexes from wild-type and HSPB1 mutants showed that the hyperactive isoforms also presented enhanced binding to client proteins. Furthermore, we show that the wild-type HSPB1 protein undergoes monomerization during heat-shock activation, strongly suggesting that the monomer is the active form of the HSPB1 protein.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.082644