SCAN: Defective protein folding in human disease: studies on ETF and implications in fatty acid metabolic disorders

Scan Seminar

Title: Defective protein folding in human disease: studies on ETF and implications in fatty acid metabolic disorders

Speaker: Bárbara Henriques, Protein Biochemistry Folding & Stability Lab

Abstract

Several human diseases result from defective protein folding, with broad effects in the cell. These can include the accumulation of toxic aggregates (like in Alzheimer’s and Parkinson’s disease), dominant negative effects (for example as a result of blockage of molecular chaperones) or loss of function resulting from unstable misfolded conformations (like in cystic fibrosis and fatty acid oxidation defects).

The Multiple Acil-coA Dehydrogenation Deficiency (MADD) is one of these conformational diseases where a loss of function is observed. This autosomal recessively inherited disorder of the mitochondrial fatty acid, amino acid, and choline metabolism, results from mutations in ETF (electron transfer flavoprotein) or in ETF:QO (ETF:ubiquinone oxidoreductase). Considerable clinical phenotypic data of various mutants is well described; still a detailed molecular understanding of the structural and functional basis of the pathology at the protein level is still necessary. In this respect, our work is focus on ETF, a heterodimeric 60 kDa protein containing FAD and AMP as cofactors.

In recent years we have been investigating the effect of different mutations in ETF (ß-D128N, -R191C, and -C42R) in respect to their effect on the folding, biological activity, conformational stability, proteolytic susceptibility and recognition by molecular chaperones during expression. In this talk I will present an overview of our experimental approach and results, and I will focus on our data on the role of flavinylation in the mild ETFß-D128N variant. We have recently established a molecular rationale for the healing effects of dietary riboflavin supplementation in some MADD patients. We have demonstrated that cofactor insertion in vitro, substantially improves not only the biological activity but also the folding, stability and the resistance to proteases, and that this could be correlated to a physiological increase in the mitochondrial FAD concentration resulting from riboflavin intake [1].

1. Henriques, B.J., et al., Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency: A molecular rationale for the effects of riboflavin supplementation. J Biol Chem, 2009 (in press).

Short CV

1997-2002 - Degree in Chemistry by the Faculdade de Ciências e Tecnologia da Universidade de Coimbra
2001-2002 - Undergraduate training at the Biological Chemistry group at FCTUC under the supervision of Prof. Rui M. Brito
2002-2004 - Graduate researcher at the Structural and Computational Biology group under supervision of Prof. Rui M. Brito at Centro de Neurociências de Coimbra
2004-2006 - Graduate researcher at Protein Biochemistry, Folding and Stability laboratory at Instituto de Tecnologia Química e Biológica
Since October of 2006 - PhD fellowship by Fundação para a Ciência e Tecnologia, on the “Structural, conformational and Functional studies in proteins: implication of protein destabilization on human pathologies” under the supervision of Prof. Cláudio M. Gomes