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David Poger

Structure, molecular dynamics and selectivity of copper and mercury metallochaperones

Published on 13 December 2005

Thesis presented December 13, 2005

Copper metallochaperones ensure delivery of Cu(I) ions towards target proteins in the cell.
Metallochaperones of the Atx1 family exhibit a high​ sequence homology and the same fold. MerP, a mercury metallochaperone​, share the same feature of sequence and structure.
This thesis aims at underlining some dynamical and structural properties responsible for selectivity of metallochaperones for Cu(I) and Hg(II). Molecular dynamics simulations of copper metallochaperones, Atx1 and Hah1, and of MerP, in their apo forms, and bound to Cu(I) or Hg(II), revealed dynamical and energetic features common to the three metallochaperones when they chelate their native metal. An interaction network between the metal-binding site loop and two other loops around the site, was identified and varies from a metalated state to another. Thus, it could define a probable selectivity for metals. The loop of the chelation site shows a great structuration in presence of metal, accompanied by a rigidifying effect if this metal is native.
X-ray absorption experiments of Cu(I) bound by Atx1 showed that Cu(I) always has a trigonal geometry whose ligands are the cysteines of the metal-binding site, and an endogenous or exogenous ligand. So Atx1 always offers Cu(I) its preferential geometry. This property is a determinant of the selectivity of Cu(I) with respect to other metals.
In presence of glutathione, the Atx1-Cu(I) complex forms a binuclear homodimer associated to two glutathione molecules. Involvement of the exogenous ligand is suggested as an in vivo selectivity factor of Atx1 for Cu(I), and could favor the recognition by Atx1 of its target protein.

Genetics, signalization, GTPase activating protein, Rac, Rho, Cdc42, cytoskeleton

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