Structural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein
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2008-12-01
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Nishida, Sonia Kiyomi 
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Transthyretin is a tetrameric binding protein involved in the transport of thyroid hormones and in the cotransport of retinol by forming a complex in plasma with retinol-binding protein. in the present study, we report the crystal structure of a macromolecular complex, in which human transthyretin, human holo-retinol-binding protein and a murine anti-retinol-binding protein Fab are assembled according to a 1 : 2 : 2 stoichiometry. the main interactions, both polar and apolar, between retinol-binding protein and transthyretin involve the retinol hydroxyl group and a limited number of solvent exposed residues. the relevance of transthyretin residues in complex formation with retinol-binding protein has been examined by mutational analysis, and the structural consequences of some transthyretin point mutations affecting protein-protein recognition have been investigated. Despite a few exceptions, in general, the substitution of a hydrophilic for a hydrophobic side chain in contact regions results in a decrease or even a loss of binding affinity, thus revealing the importance of interfacial hydrophobic interactions and a high degree of complementarity between retinol-binding protein and transthyretin. the effect is particularly evident when the mutation affects an interacting residue present in two distinct subunits of transthyretin participating simultaneously in two interactions with a retinol-binding protein molecule. This is the case of the amyloidogenic I84S replacement, which abolishes the interaction with retinol-binding protein and is associated with an altered retinol-binding protein plasma transport in carriers of this mutation. Remarkably, some of the residues in mutated human transthyretin that weaken or abolish the interaction with retinol-binding protein are present in piscine transthyretin, consistent with the lack of interaction between retinol-binding protein and transthyretin in fish.
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Febs Journal. Malden: Wiley-Blackwell, v. 275, n. 23, p. 5841-5854, 2008.