Structural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein

Structural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein

Autor Zanotti, Giuseppe Google Scholar
Folli, Claudia Google Scholar
Cendron, Laura Google Scholar
Alfieri, Beatrice Google Scholar
Nishida, Sonia Kiyomi Autor UNIFESP Google Scholar
Gliubich, Francesca Google Scholar
Pasquato, Nicola Google Scholar
Negro, Alessandro Google Scholar
Berni, Rodolfo Google Scholar
Instituição Univ Parma
Univ Padua
Venetian Inst Mol Med
Universidade Federal de São Paulo (UNIFESP)
Resumo 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.
Palavra-chave Fab
mutational analysis
protein-protein interactions
retinol-binding protein
transthyretin
Idioma Inglês
Financiador PRIN Projects of the 'Ministero dell'Universita e della Ricerca' (Rome, Italy)
Universities of Parma and Padua, Italy
Data de publicação 2008-12-01
Publicado em Febs Journal. Malden: Wiley-Blackwell, v. 275, n. 23, p. 5841-5854, 2008.
ISSN 1742-464X (Sherpa/Romeo, fator de impacto)
Publicador Wiley-Blackwell
Extensão 5841-5854
Fonte http://dx.doi.org/10.1111/j.1742-4658.2008.06705.x
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000260822700010
Endereço permanente http://repositorio.unifesp.br/handle/11600/31056

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