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The effect of celastrol, a triterpene with antitumorigenic activity, on conformational and functional aspects of the human 90 kDa heat shock protein Hsp90 alpha, a chaperone implicated in the stabilization of the tumor phenotype

Texto completo
Zanphorlin, Leticia M. [1] ; Alves, Femanda R. [1] ; Ramos, Carlos H. I. [1]
Número total de Autores: 3
Afiliação do(s) autor(es):
[1] Univ Campinas UNICAMP, Inst Chem, BR-13083970 Campinas, SP - Brazil
Número total de Afiliações: 1
Tipo de documento: Artigo Científico
Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1840, n. 10, p. 3145-3152, OCT 2014.
Citações Web of Science: 16

Background: Hsp90 is a molecular chaperone essential for cell viability in eukaryotes that is associated with the maturation of proteins involved in important cell functions and implicated in the stabilization of the tumor phenotype of various cancers, making this chaperone a notably interesting therapeutic target. Celastrol is a plant-derived pentacyclic triterpenoid compound with potent antioxidant, anti-inflammatory and anticancer activities; however, celastrors action mode is still elusive. Results: In this work, we investigated the effect of celastrol on the conformational and functional aspects of Hsp90 alpha. Interestingly, celastrol appeared to target Hsp90 alpha directly as the compound induced the oligomerization of the chaperone via the C-terminal domain as demonstrated by experiments using a deletion mutant The nature of the oligomers was investigated by biophysical tools demonstrating that a two-fold excess of celastrol induced the formation of a decameric Hsp90 alpha bound throughout the C-terminal domain. When bound, celastrol destabilized the C-terminal domain. Surprisingly, standard chaperone functional investigations demonstrated that neither the in vitro chaperone activity of protecting against aggregation nor the ability to bind a TPR co-chaperone, which binds to the C-terminus of Hsp90 alpha, were affected by celastrol. Conclusion: Celastrol interferes with specific biological functions of Hsp90 alpha. Our results suggest a model in which celastrol binds directly to the C-terminal domain of Hsp90 alpha causing oligomerization. However, the ability to protect against protein aggregation (supported by our results) and to bind to TPR co-chaperones are not affected by celastrol. Therefore celastrol may act primarily by inducing specific oligomerization that affects some, but not all, of the functions of Hsp90 alpha. General significance: To the best of our knowledge, this study is the first work to use multiple probes to investigate the effect that celastrol has on the stability and oligomerization of Hsp90 alpha and on the binding of this chaperone to Tom70. This work provides a novel mechanism by which celastrol binds Hsp90 alpha. (C) 2014 Elsevier B.V. All rights reserved. (AU)

Processo FAPESP: 12/50161-8 - Estudo da estrutura e função da chaperona Hsp90 com ênfase no seu papel em homeostase celular
Beneficiário:Carlos Henrique Inacio Ramos
Linha de fomento: Auxílio à Pesquisa - Temático