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    ABSTRACT: Fe-S cluster biogenesis is an essential pathway coordinated by a network of protein-protein interactions whose functions include desulfurase activity, substrate delivery, electron transfer and product transfer. In an effort to understand the intricacies of the pathway, we have developed an in vitro assay to follow the ferredoxin role in electron transfer during Fe-S cluster assembly. Previously, assays have relied upon the non-physiological reducing agents dithionite and dithiothreitol to assess function. We have addressed this shortcoming by using electron transfer between NADPH and ferredoxin-NADP-reductase to reduce ferredoxin. Our results show that this trio of electron transfer partners are sufficient to sustain the reaction in in vitro studies, albeit with a rate slower compared with DTT-mediated cluster assembly. We also show that, despite overlapping with the CyaY protein in binding to IscS, Fdx does not interfere with the inhibitory activity of this protein. We suggest explanations for these observations which have important consequences for understanding the mechanism of cluster formation. Cofactor-dependent proteins: evolution, chemical diversity and bio-applications. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Feb 2015 · Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics
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    ABSTRACT: The problem of distinguishing causes from effects is not a trivial one, as illustrated by the science fiction writer Isaac Asimov in a novel dedicated to an imaginary compound with surprising "chronochemistry" properties. The problem is particularly important when trying to establish the etiology of diseases. Here, we discuss how the problem reflects on our understanding of disease using two specific examples: Alzheimer's disease (AD) and Friedreich's ataxia (FRDA). We show how the fibrillar aggregates observed in AD were first denied any interest, then to assume a central focus, and to finally recess to be considered the dead-end point of the aggregation pathway. This current view is that the soluble aggregates formed along the aggregation pathway rather than the mature amyliod fiber are the causes of disease, Similarly, we illustrate how the identification of causes and and effects have been important in the study of FRDA. This disease has alternatively been considered as the consequence of oxidative stress, iron precipitation or reduction of iron-sulfur cluster protein context. We illustrate how new tools have recently been established which allow us to follow the development of the disease. We hope that this review may inspire similar studies in other scientific disciplines.
    Full-text · Article · Mar 2014 · Frontiers in Molecular Neuroscience
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    ABSTRACT: Migraine headaches are a common comorbidity in Rolandic Epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 (multipoint HLOD 4.40 (heterogeneity LOD), recessive, 99% penetrance), replicated in the second dataset (HLOD 2.61); and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (2PT LOD 3.00, MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees re-analyzed for linkage.
    Full-text · Article · Nov 2013 · Genes Brain and Behavior
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