3BT0

Crystal structure of transthyretin variant V20S

Summary for 3BT0

• Entry DOI: 10.2210/pdb3bt0/pdb
• Related: 1F41 2G4E 2NOY 3BSZ
• Descriptor: Transthyretin (2 entities in total)
• Functional Keywords: ttr, amyloid fibrils, point mutation, transport protein
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27530.62

Authors

Zanotti, G.,Folli, C.,Cendron, L.,Gliubich, F.,Negro, A.,Berni, R. (deposition date: 2007-12-27, release date: 2008-11-11, Last modification date: 2023-11-01)

Primary citation

Zanotti, G.,Folli, C.,Cendron, L.,Alfieri, B.,Nishida, S.K.,Gliubich, F.,Pasquato, N.,Negro, A.,Berni, R.
Structural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein.
Febs J., 275:5841-5854, 2008

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.

PubMed: 19021760
DOI: 10.1111/j.1742-4658.2008.06705.x

Experimental method

X-RAY DIFFRACTION (1.59 Å)