Structural studies of the protein endostatin in fusion with BAX BH3 death domain, a hybrid that presents enhanced antitumoral activity

Autor(es)

Chura-Chambi, Rosa Maria ; Arcuri, Helen Andrade ; Lino, Felipe ; Versati, Natan ; Palma, Mario Sergio ; Favaro, Denize C. ; Morganti, Ligia

• Tipo de documento: Artigo Científico
• Fonte: Biotechnology and Applied Biochemistry; v. 64, n. 3, p. 356-363, MAY-JUN 2017.
• Citações Web of Science: 0

Resumo

Endostatin (ES) is an antiangiogenic protein that exhibits antitumor activity in animal models. However, the activity observed in animals was not observed in human clinical trials. ES - BAX is a fusion protein composed of two functional domains: ES, which presents specificity and is internalized by activated endothelial cells and the proapoptotic BH3 domain of the protein BAX, a peptide inductor of cellular death when internalized. We have previously shown (Chura - Chambi et al., Cell Death Dis, 5, e1371, 2014) that ES - BAX presents improved antitumor activity in relation to wild - type ES. Secondary and tertiary structures of ES - BAX are similar to ES, as indicated by homology - modeling studies and molecular dynamics simulations. Tryptophan intrinsic fluorescence and circular dichroism spectroscopy corroborate these data. 15N HSQC NMR indicates that ES - BAX is structured, but some ES residues have suffered chemical shift perturbations, suggesting that the BH3 peptide interacts with some parts of the ES protein. ES and ES - BAX present similar stability to thermal denaturation. The production of stable hybrid proteins can be a new approach to the development of therapeutic agents presenting specificity for tumoral endothelium and improved antitumor effect. (C) 2016 International Union of Biochemistry and Molecular Biology, Inc. (AU)

• Processo FAPESP: 03/07949-4 - Estudo de atividade antiangiogenica de proteinas de fusao endostatina-peptideos com atividade apoptotica.
• Beneficiário: Ligia Ely Morganti Ferreira Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 07/54624-4 - Estudos de renaturação em alta pressão hidrostática de proteínas agregadas em corpos de inclusão citoplasmáticos produzidos em Escherichia coli
• Beneficiário: Ligia Ely Morganti Ferreira Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular