Browsing by Author "Lages, Ana"
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- Insights into the molecular mechanism of protein native-like aggregation upon methylglyoxal glycationPublication . Oliveira, Luís M. A.; Gomes, Ricardo A.; Yang, Dennis; Família, Carlos; Lages, Ana; Coelho, Ana V.; Murphy, Regina M.; Quintas, Alexandre"Protein glycation induces structural and stability changes that impair protein function, and is associated with several human neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and Familial Amyloidotic Polyneuropathy. Recently we have shown that methylglyoxal induces and stabilizes the formation of small native-like aggregates in the amyloidogenic protein insulin and the same was previously shown for α-synuclein. However, the fundamental biophysical mechanism underlying such methylglyoxal-induced protein aggregation is not yet fully understood. In this study, we used the model protein cytochrome c to characterize the specific glycation targets and to investigate the glycation effects on protein structure, stability and aggregation. Methylglyoxal was found modify cytochrome c in a single residue and to induce the formation of cytochrome c native-like aggregates. Additionally, it is shown that methylglyoxal glycation of cytochrome c also results in the formation of a partially unfolded species. Interestingly, the formation of this partially unfolded species is not implicated in the aggregation process, a clear difference from amyloid fibril mechanisms that involve partially or totally unfolded intermediates. Equilibrium-unfolding experiments using guanidinium hydrochloride shows that glycation strongly reduces cytochrome c conformational stability. This reduction is balanced by aggregation that increases conformational stability. The data collected from analytical and spectroscopic techniques along with kinetic analysis based on least-squares parameter fitting and statistical model discrimination permitted the proposal of a comprehensive thermodynamic and kinetic model for native-like aggregation of methylglyoxal glycated cytochrome c."
- Insulin glycation by methylglyoxal results in native-like aggregation and inhibition of fibril formationPublication . Oliveira, Luis MA; Lages, Ana; Gomes, Ricardo A; Neves, Henrique; Família, Carlos; Coelho, Ana V; Quintas, AlexandreBackground: Insulin is a hormone that regulates blood glucose homeostasis and is a central protein in a medical condition termed insulin injection amyloidosis. It is intimately associated with glycaemia and is vulnerable to glycation by glucose and other highly reactive carbonyls like methylglyoxal, especially in diabetic conditions. Protein glycation is involved in structure and stability changes that impair protein functionality, and is associated with several human diseases, such as diabetes and neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease and Familiar Amyloidotic Polyneuropathy. In the present work, methylglyoxal was investigated for their effects on the structure, stability and fibril formation of insulin.
- Transthyretin Proteins Regulate Angiogenesis by Conferring Different Molecular Identities to Endothelial CellsPublication . Nunes, Raquel J.; Oliveira, Paula de; Lages, Ana; Becker, Jörg D.; Marcelino, Paulo; Barroso, Eduardo; Perdigoto, Rui; Kelly, Jeffery W.; Quintas, Alexandre; Santos, Susana C. R."Background: The biological effects of transthyretin proteins on vasculature remain unknown. Results: V30M transthyretin tetramer modulates endothelial global gene expression, down-regulating pro-angiogenic genes, inducing apoptosis and inhibiting migration. Conclusion: Transthyretin proteins regulate angiogenesis by conferring different molecular identities to endothelial cells. Significance: This work has critical implications in the prevention of early hepatic artery thrombosis in familial amyloidotic polyneuropathy patients after liver transplantation."