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Etudes des ATPases AAA+ ATAD3A et ATAD3B

Abstract : ATAD3A is part of a novel family of mitochondrial AAA+ ATPase (ATPases Associated to diverse cellular Activities) specific to the multicellular eukaryotes (1). In the laboratory, we have identified ATAD3A as a specific target for the Ca2+/Zn2+-binding S100B protein (2). In the Hominidae, there is a second member of the ATAD3 family, the mitochondrial protein ATAD3B. The aim of my thesis was to solve the mitochondrial topology of ATAD3A and ATAD3B and to study their functions and interactions. We have shown that these two proteins are anchored in the inner mitochondrial membrane at the contact sites with the external membrane and that they form hexameric complexes. We have then shown that ATAD3B is specifically expressed in the human embryonic stem cells and is re-expressed in iPs (induced Pluripotent stem cell) and certain cancer cell lines. Complimentary studies were done using the down regulation of ATAD3B by shRNA and expression of dominant-negative ATAD3A mutants in the human lung cancer cell line, H1299. Our results suggest that ATAD3B interacts and forms hetero-oligomers with ATAD3A. ATAD3B seems to behave like a dominant negative of ATAD3A. To have a better understanding of the function of ATAD3A in vivo, we developed models in Drosophila with which results show that ATAD3A is required for cell growth and organism development. (1): Gilquin et al. The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes. (Mol Cell Biol. 2010 Apr;30(8):1984-96) (2): Gilquin et al. The calcium-dependent interaction between S100B and the mitochondrial AAA-ATPase ATAD3A and the role of this complex in the cytoplasmic processing of ATAD3A. (Mol Cell Biol. 2010 Mar 29) STAR
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Nicolas Merle. Etudes des ATPases AAA+ ATAD3A et ATAD3B. Sciences agricoles. Université de Grenoble, 2011. Français. ⟨NNT : 2011GRENV069⟩. ⟨tel-00684481⟩

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