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Structural study on ligand specificity of human vitamin B12 transporters

Abstract : Studies comparing the binding of genuine cobalamin (vitamin B12) to that of its natural or synthetic analogues have long established increasing ligand specificity in the order haptocorrin, transcobalamin and intrinsic factor, the high-affinity binding proteins involved in cobalamin transport in mammals. Here, ligand specificity is investigated from a structural point of view, for which comparative models of intrinsic factor and haptocorrin are produced based on the crystal structure of the homologous transcobalamin and validated by results of published binding assays. Many interactions between cobalamin and its binding site in the interface of the two domains are conserved among the transporters. A structural comparison suggests that the determinant of specificity regarding cobalamin ligands with modified nucleotide moiety resides in the {beta}-hairpin motif {beta}3-turn-{beta}4 of the smaller C-terminal domain. In haptocorrin, it provides hydrophobic contacts to the benzimidazole moiety through the apolar part of Arg357, Trp359 and Tyr362. Together, these large side chains may compensate for the missing nucleotide upon cobinamide binding. Intrinsic factor possesses only the Trp and transcobalamin only the Tyr, consistent with their low affinity for cobinamide. Relative affinity constants for other analogues are rationalized similarly by analysis of steric and electrostatic interactions with the three transporters. The structures also indicate that the C-terminal domain is the first site of cobalamin-binding since part of the {beta}-hairpin motif is trapped between the nucleotide moiety and the N-terminal domain in the final holo-proteins.
Mots-clés : Life Sciences
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Submitted on : Friday, April 30, 2010 - 3:49:25 PM
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Jochen Wuerges, Silvano Geremia, Lucio Randaccio. Structural study on ligand specificity of human vitamin B12 transporters. Biochemical Journal, Portland Press, 2007, 403 (3), pp.431-440. ⟨10.1042/BJ20061394⟩. ⟨hal-00478662⟩



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