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Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-tooth neuropathy

(2010) JOURNAL OF BIOLOGICAL CHEMISTRY. 285(17). p.12778-12786
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Abstract
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 wildtype HSPB1 protein undergoes monomerization during heat-shock activation, strongly suggesting that the monomer is the active form of the HSPB1 protein.
Keywords
MUTATION, ALPHA-CRYSTALLIN DOMAIN, SUBUNIT INTERACTIONS, A-CRYSTALLIN, IN-VIVO, DISSOCIATION, HSP27, HEAT-SHOCK-PROTEIN, B-CRYSTALLIN, CHAPERONE ACTIVITY

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Citation

Please use this url to cite or link to this publication:

Chicago
Almeida-Souza, Leonardo, Sofie Goethals, Vicky de Winter, Ines Dierick, Rodrigo Gallardo, Joost Van Durme, Joy Irobi, et al. 2010. “Increased Monomerization of Mutant HSPB1 Leads to Protein Hyperactivity in Charcot-Marie-tooth Neuropathy.” Journal of Biological Chemistry 285 (17): 12778–12786.
APA
Almeida-Souza, L., Goethals, S., de Winter, V., Dierick, I., Gallardo, R., Van Durme, J., Irobi, J., et al. (2010). Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-tooth neuropathy. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(17), 12778–12786.
Vancouver
1.
Almeida-Souza L, Goethals S, de Winter V, Dierick I, Gallardo R, Van Durme J, et al. Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-tooth neuropathy. JOURNAL OF BIOLOGICAL CHEMISTRY. 2010;285(17):12778–86.
MLA
Almeida-Souza, Leonardo, Sofie Goethals, Vicky de Winter, et al. “Increased Monomerization of Mutant HSPB1 Leads to Protein Hyperactivity in Charcot-Marie-tooth Neuropathy.” JOURNAL OF BIOLOGICAL CHEMISTRY 285.17 (2010): 12778–12786. Print.
@article{943547,
  abstract     = {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 wildtype HSPB1 protein undergoes monomerization during heat-shock activation, strongly suggesting that the monomer is the active form of the HSPB1 protein.},
  author       = {Almeida-Souza, Leonardo and Goethals, Sofie and de Winter, Vicky and Dierick, Ines and Gallardo, Rodrigo and Van Durme, Joost and Irobi, Joy and Gettemans, Jan and Rousseau, Frederic and Schymkowitz, Joost and Timmerman, Vincent and Janssens, Sophie},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keyword      = {MUTATION,ALPHA-CRYSTALLIN DOMAIN,SUBUNIT INTERACTIONS,A-CRYSTALLIN,IN-VIVO,DISSOCIATION,HSP27,HEAT-SHOCK-PROTEIN,B-CRYSTALLIN,CHAPERONE ACTIVITY},
  language     = {eng},
  number       = {17},
  pages        = {12778--12786},
  title        = {Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-tooth neuropathy},
  url          = {http://dx.doi.org/10.1074/jbc.M109.082644},
  volume       = {285},
  year         = {2010},
}

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