A 18 months post-doctoral fellowship is available in the “Biocatalysis” team (lead by Dr S. Ollagnier de Choudens) of the LCBM that works on the reactivity of systems involved in the assembly of complex inorganic structures involving biochemists and biologists. The project is financed by the French “Agence Nationale de la Recherche” (ANR).
The Laboratory of Chemistry and Biology of Metals (LCBM) is a mixed laboratory (CEA, CNRS, the University J. Fourier) that takes part of the iRTSV institute at the CEA of Grenoble. The laboratory, at the interface between chemistry and biology, focuses on the study of the structure, activity and regulation of complex biological systems using or transporting metals.
Summary of the project:
Background. 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, have not been clearly identified, although experimental data suggest that frataxin and ferredoxin proteins are involved,
respectively. We have recently demonstrated that frataxin plays a crucial role in the early steps of Fe-S biogenesis by controlling within a big complex formed by the cysteine desulfurase, the scaffold and frataxin, the iron entry through activation of the cysteine desulfurase. 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.
Project. 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 involving frataxin protein and leading to formation of Fe-S clusters within the scaffold protein before Fe-S delivery to targets. We would like to have a better understanding of the molecular mechanism involved in generating Fe2S2 and Fe4S4 clusters on the scaffold, in particular the control of iron entry by frataxin protein through sulfur production by the cysteine desulfurase, and the role of ferredoxin as electron donor. This fundamental research proposal will address these questions through a multidisciplinary approach, combining biochemistry, biophysics and structural data. The combination of in vitro studies associated with in vivo ones in the animal by our collaborators, will allow to shed light to this fundamental essential cellular pathway implicated in various human diseases.
- Colin, F.; Martelli, A.; Clemancey, M.; Latour, J. M.; Gambarelli, S.; Zeppieri, L.; Birck, C.; Page, A.; Puccio, H.; Ollagnier de Choudens, S. Journal of the American Chemical Society 2013, 135, 733.
- Schmucker, S.; Martelli, A.; Colin, F.; Page, A.; Wattenhofer-Donze, M.; Reutenauer, L.; Puccio, H. PLoS One 2011, 6, e16199.
- Schmucker, S.; Puccio, H. Hum. Mol. Genet. 2010, 19, R103.
- Beilschmidt, L. K.; Puccio, H. M. Biochimie 2014, 100, 48.
Candidates should have a strong expertise in biochemistry, a good background in enzymology and molecular biology, and an interest for structural biology and spectroscopy. Candidates should preferably have defended their PhD in the last 2 years.
Applications should be sent to Sandrine Ollagnier ()
Expires on Tuesday September 1st, 2015