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Accueil > Animation scientifique & Evénements > Conférences CICB-Paris > Archives des conférences CICB-Paris de 2015

Inorganic Chemistry of Cellular Decision Making Processes : Metallome Changes in Normal and Pathological States

par Marie Körner - publié le , mis à jour le

par Prof. Thomas V. O’Halloran
The Chemistry of Life Processes Institute,Lurie Comprehensive Cancer Center, Departments of Chemistry and Molecular Biosciences, Northwestern University, Evanston Il, USA

Cette conférence est organisée le 16 avril 2015, à 11h, dans l’amphithéâtre Giroud

Résumé de la conférence :

All cells must acquire a variety of transition metal ions until they achieve a precise level known as the metal quota. The ensemble of metal concentrations is then referred to as the metallome of the cell[1]. As the nature of the metallome is revealed for different types of cells, we are finding a general pattern of metal ion utilization that is highly conserved across evolution. These patterns of metal utilization are perturbed in the earliest stage of mammalian developmental states, in infectious disease and cancer cell proliferation. A large number of specialized proteins are required to maintain the intracellular quota for each metal within a narrow range. While most metals are bound tightly in a variety of well characterized metalloenzyme active sites, recent studies of the emerging class of metal homeostasis proteins reveal new types of biological coordination chemistry and are opening new questions about how specialized and aberrant cells sense, acquire and deploy these metal ions [2]. This talk will focus on understanding how changes in the metallome control or reflect key programmatic decisions the cell must make, such as proliferation, senescence, apoptosis, cell cycle progression.

The metallome is maintained in part via specific metalloregulatory proteins, which sense changes in metal availability and turn on or off specific genes. Studies of metalloregulatory proteins reveal novel coordination chemistry that gives rise to extreme thermodynamic sensitivity : these proteins sense changes in zinc concentration in the femtomolar range1 or copper in the zeptomolar range[3], and then adjust the transcription of metal homeostasis genes in a manner that keeps free metal ion concentrations in the cytosol at vanishing low levels. Cells control metal availability through a family of proteins which facilitate trafficking of metals within the cell, namely metallochaperone proteins[4]. The chemistry of these systems serves a foundation for understanding the inorganic chemistry of the cell, we are now focusing on how tumors and pathogens battle with host cells for control over metal availability [5]. Analytical methods including STEM-EDS/EELS, ICP-MS, X-ray fluorescence microscopy and new fluorescent metal-specific probes reveal connections between subcellular distribution of metals and proteins that insure appropriate metal trafficking. Cases where changes in metal ion signatures play a central role in physiology will be described including ones important in mammalian developmental biology [6,7].

1. Outten, CE, O’Halloran, TV, "Femtomolar Sensitivity of Metalloregulatory Proteins Controlling Zinc Homeostasis." Science 2001, June 29 ;292 (5526) : 2488-92.
2. Davis, AV, O’Halloran, TV, "A Place for Thioether Chemistry in Cellular Copper Ion Recognition and Trafficking." Nature Chemical Biology, 2008, 4, 148-151.
3. Changela, A. et al. "Molecular Basis of Selectivity and Zeptomolar Sensitivity by CueR" Science, 2003, 301, 1383-1387.
4. Pufahl, RA, et al. "Metal Ion Chaperone Function of the Soluble Cu(I) Receptor, Atx1" Science, 1997, 278, 853-856.
5. Simm C, Luan CH, Weiss E, O’Halloran TV. High-throughput screen for indentifying small molecules that target fungal zinc homeostasis. PLoS One. 2011 ;6(9):e25136. PMC3182986
6. Kim, AM, et al. “Zinc Availability Regulates Exit From Meiosis in Maturing Mammalian Oocytes.” Nature Chem Biol 2010 Sep,6(9) ;674-81.
7. Que EL, et al. Quantitative mapping of zinc fluxes in the mammalian egg reveals the origin of fertilization-induced zinc sparks. Nature Chem (2015) doi:10.1038/nchem.2133. NIHMS642165. PMCID : PMC4315321.

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