Download MendeleyStructural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein.
Zanotti, G., Folli, C., Cendron, L., Alfieri, B., Nishida, S.K., Gliubich, F., Pasquato, N., Negro, A., Berni, R.(2008) FEBS J 275: 5841-5854
- PubMed: 19021760
- DOI: https://doi.org/10.1111/j.1742-4658.2008.06705.x
- Primary Citation of Related Structures:
3BSZ, 3BT0, 3CXF - PubMed Abstract:
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.
Organizational Affiliation:
Department of Chemical Sciences and Institute of Biomolecular Chemistry-CNR, University of Padua, Italy. [email protected]
