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Mécanisme, catalyse et spécificité structurale des Méthionine Sulfoxyde Réductases de classe A et caractérisation de disulfure oxydoréductases de Neisseria meningitidis

Abstract : The periplasmic protein PilB is described to be involved in vivo in the resistance of pathogens from Neisseria genus to hydrogen peroxide generated by the host macrophages. PilB is composed of three domains : the N-ter domain (N-ter) that display a disulfure oxidoreductase activity, the central and the C-terminal that display methionine sulfoxide reductase A and B activities. MsrA and MsrB catalyse the reduction of protein bound methionine sulfoxide (MetSO) back to methionine (Met). These two classes of Msr A and B are structurally unrelated and are specific for the reduction of the S and R isomer of the sulfoxide function respectively. They share a similar catalytic mechanism consisting of three steps that involve the formation of a sulfenic acid intermediate followed by the formation of an intramolecular disulfide bond that is then reduced by thioredoxin for cytoplasmic Msrs and by the N-ter domain for the Msrs domain of the PilB protein. The N-ter domain display a DsbE fold. These proteins are periplasmic disulfure oxidoreductases involved in the cytochrome c maturation pathway. The results obtained during my PhD have lead to the characterisation of residues of the actove site of Neisseria meningitidis involved in the recognition of the sulfoxide substrate and in the catalysis of the reductase step. The study of periplasmic disulfure oxidoreductases from N. meningitidis was undertaken in order to characterise in vitro the DsbE from N. meningitidis. The structural and molecular factors involved in the recognition of their targets and/or partners could then be determined.
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Adeline Gand. Mécanisme, catalyse et spécificité structurale des Méthionine Sulfoxyde Réductases de classe A et caractérisation de disulfure oxydoréductases de Neisseria meningitidis. Biologie moléculaire. Université Henri Poincaré - Nancy 1, 2008. Français. ⟨NNT : 2008NAN10031⟩. ⟨tel-01748520⟩

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