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Biophysical studies suggest a new structural arrangement of crotoxin and provide insights into its toxic mechanism

Texto completo
Autor(es):
Fernandes, Carlos A. H. ; Pazin, Wallance M. ; Dreyer, Thiago R. ; Bicev, Renata N. ; Cavalcante, Walter L. G. ; Fortes-Dias, Consuelo L. ; Ito, Amando S. ; Oliveira, Cristiano L. P. ; Fernandez, Roberto Morato ; Fontes, Marcos R. M.
Número total de Autores: 10
Tipo de documento: Artigo Científico
Fonte: SCIENTIFIC REPORTS; v. 7, MAR 3 2017.
Citações Web of Science: 1
Resumo

Crotoxin (CTX) is the main neurotoxin found in Crotalus durissus rattlesnake venoms being composed by a nontoxic and non-enzymatic component (CA) and a toxic phospholipase A(2) (CB). Previous crystallographic structures of CTX and CB provided relevant insights: (i) CTX structure showed a 1:1 molecular ratio between CA and CB, presenting three tryptophan residues in the CA/CB interface and one exposed to solvent; (ii) CB structure displayed a tetrameric conformation. This study aims to provide further information on the CTX mechanism of action by several biophysical methods. Our data show that isolated CB can in fact form tetramers in solution; however, these tetramers can be dissociated by CA titration. Furthermore, CTX exhibits a strong reduction in fluorescence intensity and lifetime compared with isolated CA and CB, suggesting that all tryptophan residues in CTX may be hidden by the CA/CB interface. By companying spectroscopy fluorescence and SAXS data, we obtained a new structural model for the CTX heterodimer in which all tryptophans are located in the interface, and the N-terminal region of CB is largely exposed to the solvent. Based on this model, we propose a toxic mechanism of action for CTX, involving the interaction of N-terminal region of CB with the target before CA dissociation. (AU)

Processo FAPESP: 15/17286-0 - Estudos estruturais e funcionais objetivando compreender o papel de toxinas de venenos de serpentes e de como inibir a sua atividade biológica
Beneficiário:Marcos Roberto de Mattos Fontes
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 13/17864-8 - Estudos estruturais de fosfolipases A2 neurotóxicas
Beneficiário:Carlos Alexandre Henrique Fernandes
Linha de fomento: Bolsas no Brasil - Pós-Doutorado