Version française
Institutes/ Institute of life sciences research and technologies (iRTSV)/ Unités / Chimie et Biologie des Métaux (CBM)/ Biology of metals

Biology of metals



Team leader
 
 
 Isabelle Michaud-Soret
CEA Grenoble,
iRTSV/LCBM/BioMet
17 rue des Martyrs
38 054 Grenoble cedex 09
Phone: (33) 4 38 78 99 40

Secretary:
Phone: (33) 4 38 78 40 95
Fax: (33) 4 38 78 54 87
 
Proposal for a codirected funded thesis in our team.
 
Team members
 
Permanent scientists:
Mohamed Benharouga
Alexandre Bouron,
Patrice Catty
Peggy Charbonnier
Mireille Chevallet
Martine Cuillel
Isabelle Michaud-Soret
Élisabeth Mintz
Roger Miras

Temporary scientists:
Sandra Galop, PhD thesis 2011-
Elaine Hilario Da Souza, co-directed thesis with Brazil, 2011-
Caroline Fauquant-Pecqueur, scientist 2011-
Sophie Mathieu, post-doctoral fellow 2011-
Amélie Harel, professional license course 2012



Picture legend, from left to right:
back: Alexandre Bouron, Patrice Catty, Martine Cuillel, Mohamed Benharouga, Caroline Fauquant-Pecqueur, Mireille Chevallet, Isabelle Michaud-Soret
front: Sandra Galop, Élisabeth Mintz, Sophie Mathieu, Amélie Harel, Roger Miras, Elaine Hilario Da Souza
insert: Peggy Charbonnier.
 
Presentation
 
The "Biology of Metals" or BioMet team focuses on the molecular and cellular mechanisms responsible for intracellular traffic, storage and regulation of various metal ions; the group studies the homeostasis of some essential metals such as copper, iron and zinc in prokaryotic and eukaryotic cells.

Our work is devoted to the study of detoxification and homeostasis of cadmium, calcium, copper, iron, zinc, cobalt and nickel metal ions in the cell. While cadmium is purely toxic, other elements are essential to cellular functions. However essential metal may, in case of deficiency or excess, compromise cell survival. Metallic cations are bound to a set of biomolecules that control their detection, transport, bioavailability and, possibly, their intracellular storage. The cellular homeostasis of these metals is finely regulated at the level of gene expression and protein synthesis.



The BioMet team studies several proteins which bind metallic cations and transfer them (i.e. exchange the metallic cations) to specific metalloproteins, some of them are able to interact with DNA or RNA to control gene expression or protein synthesis.

Within this framework, we focus on several membrane proteins whose function is to transport copper ions for one, chloride ions for another, and whose dysfunctionings are responsible for serious diseases in humans, such as Wilson's disease and cystic fibrosis. Our work focuses also on other membrane proteins responsible for transporting metals (TRP channels as TPRC6 and TRPM7 and P-type ATPases). Another concern of ours is the regulation of metal homeostasis by bacterial transcriptional regulators and eukaryotic translational regulators involved in the homeostatic control of iron and nickel. Studies of these regulatory systems, especially in stress conditions (metallic, oxidative or, for example associated with exposure to nanoparticles or other chemical molecules) is of particular interest to understand the metabolic disturbances caused.

Our research topics concern mainly fundamental research to better understand the mechanisms that regulate the intracellular concentration of the mentioned metals and the intracellular localization of membrane transporters. This is essential to understanding at the cellular and molecular level various pathologies related to dysregulation of metal homeostasis. Our work can also serve to identify new targets to fight the virulence of pathogenic bacteria. However, some research topics concern more finalized aspects as the search for antibacterial agents targeting the main regulator of iron homeostasis, the study of chelators for the removal of copper accumulation in the liver, the effect of an antidepressant on the brain zinc homeostasis or the toxicology of metallic nanoparticles.

Our axes of research aim to understand:
• the mechanism of heavy metal transport (Cd2+, Co2+, Cu+) through P1-ATPases and other efflux pumps

• the Cu+ delivery to the secretory pathway and the elimination of the excesses of Cu+ with the help of specific intracellular chelators

• the intracellular trafficking of transmembrane carriers - addressing, localization changes, degradation (human genetic diseases : Wilson's disease and cystic fibrosis)

l• the mechanisms of cross-regulatory network of Fur and NikR proteins, bacterial transcriptional metalloregulators and their involvement in the virulence of pathogenic bacteria (search of anti-Fur inhibitors with antibacterial aim)

• the transmembrane transport and storage of zinc ions in neurons, especially the involvement of cation channels such as TRPC6 channels in the transport of zinc

• the disruption of iron homeostasis and metal homeostasis and consequences in eukaryotes

• the interferences between metallic nanoparticles and metal homeostasis (LCBM transversal project involving several groups).
 
Keywords
 
Metal - cells - homeostasis - detoxification - membranes - transporters - intracellular traffic - degradation - proteins - binding sites - metalloregulator - bioinorganic - regulation of expression - coordination - ionic selectivity - Wilson's disease - cystic fibrosis - TRP channels.
 
Techniques
 
Molecular biology - site directed mutagenesis - heterologous expression in various systems (bacteria, yeast, insect and mammal cells) - primary or not cell cultures - purification of proteins - biochemistry - protein chemistry - light scattering - labelling - absorption spectroscopies, fluorescence, circular dichroism - enzymology - metabolic radiolabelling (pulse chase) - cellular imagery - electrophysiology.
 
Collaborations
 

- local: CEA-iRTSV, CEA-INAC, CEA-IBS, ESRF, EFS, CHU-DBI, CHU-Pneumology, IAB, GIN, UJF-DCM, UJF-DPM

- national: ENS (Lyon), INSERM-UMR-S 757 (Orsay), CNRS UMR 7178 (Strasbourg), Institut du thorax (Nantes), CEA-iBiTec-S (Saclay), CEA-iBEB (Cadarache), CEA-iRCM (Fontenay)

- international: 15 in Europe (5 Deutschland, 2 Greece, 1 Italy, 1 Norway, 2 Portugal, 2 Switzerland, 2 United-Kingdom), 5 in America (1 Brazil, 2 Canada, 2 USA), 1 in Asia (Japan)