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ANR funded project

Une nouvelle représentation du vivant (DS0401) 2014
Projet FRATISCA

Deciphering early and late stages of mammalian mitochondrial Fe-S cluster assembly.

Iron-sulfur (Fe-S) cluster-containing proteins are essential components of the cell, involved in numerous physiological processes ranging from nuclear genome synthesis and stability, protein translation to mitochondrial metabolism and respiration. Within the past decade, the biogenesis of Fe-S proteins has been extensively studied by genetic and biochemical approaches in bacteria and in yeast, and more recently in plants and mammals, demonstrating that it is a complex process involving multiple components, highly conserved from the bacterial to humans. The process of Fe-S protein maturation is a fundamental and essential biosynthetic pathway. In humans, mutations in several components of this biosynthetic machinery are associated with severe disorders such as neurodegeneration, myopathy and anemia, pointing to the importance of this pathway for normal cellular function. In eukaryotes, the initial stage of nascent Fe-S cluster biosynthesis occurs within the mitochondria, by a multimeric protein complex, involving the assembly of a transiently-bound Fe-S cluster on a scaffold protein from inorganic sulfur and iron. The sulfur is provided by an enzymatic activity carried by a cysteine desulfurase. The source of iron and electrons, required in this process, have not been clearly identified, although experimental data suggest that frataxin and ferredoxin are involved, respectively. We have recently demonstrated that frataxin plays a crucial role in the early steps of Fe-S biogenesis by controling within a big complex formed by the cysteine desulfurase complex, the scaffold and frataxin, the iron entry through activation of the cysteine desulfurase. Its is also essential to properly assemble and protect the Fe-S cluster within the scaffold protein. These results provide consolidated information about the role of frataxin for nascent Fe-S cluster biosynthesis, and open up a new path to further unravel the molecular mechanism involved in nascent Fe-S cluster synthesis. Once assembled, the labile Fe-S cluster on the scaffold protein is transferred to target mitochondrial proteins with the help of accessory proteins and factors. The protein involved and the molecular mechanism underlying this transfer are poorly characterized. In the present proposal, our objectives are to get new insights into the mammalian mitochondrial Fe-S machinery, with a specific focus on the initial stages of Fe-S cluster assembly leading to formation of Fe-S clusters within a dedicated scaffold protein as well as the subsequent steps leading to the delivery of Fe-S clusters to mitochondrial Fe-S proteins. This fundamental research proposal will address these questions through a multidisciplinary approach, combining biochemistry, biophysics and structural data with physiological and molecular studies in the animal. The combination of in vitro and in vivo approaches to understand the function of the proteins and the molecular mechanisms involved is a plus value, essential to shed light to this important central process of Fe-S biogenesis.

Partners

IBS Institut de Biologie Structurale /Groupe Métalloprotéines

IGBMC INSTITUT DE GENETIQUE ET DE BIOLOGIE MOLECULAIRE ET CELLULAIRE

CEA/DSV:iRTSV/LCBM Laboratoire de Chimie et Biologie des Métaux

CNRS/CEA/UJF/Biocat Laboratoire de Chimie et Biologie des Métaux

ANR grant: 550 000 euros
Beginning and duration: octobre 2014 - 36 mois

 

ANR Programme: Une nouvelle représentation du vivant (DS0401) 2014

Project ID: ANR-14-CE09-0026

Project coordinator:
Madame Helene Puccio (INSTITUT DE GENETIQUE ET DE BIOLOGIE MOLECULAIRE ET CELLULAIRE)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.