Structural studies of the protein endostatin in fusion with BAX BH3 death domain, a hybrid that presents enhanced antitumoral activity
Nenhuma Miniatura disponível
Data
2017-05-01
Autores
Chura-Chambi, Rosa Maria
Arcuri, Helen Andrade
Lino, Felipe
Versati, Natan
Palma, Mario Sergio [UNESP]
Favaro, Denize C.
Morganti, Ligia
Título da Revista
ISSN da Revista
Título de Volume
Editor
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.
Descrição
Palavras-chave
angiogenesis, apoptosis, BAX, BH3 domain, circular dichroism, endostatin, molecular modeling
Como citar
Biotechnology and Applied Biochemistry, v. 64, n. 3, p. 356-363, 2017.