The transthyretin-retinol-binding protein complex

doi:10.1016/S0167-4838(00)00140-0

Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology

Volume 1482, Issues 1–2, 18 October 2000, Pages 65-72

Biochimica et Biophy...

https://doi.org/10.1016/S0167-4838(00)00140-0 Get rights and content

Abstract

Transthyretin (TTR, formerly called prealbumin), one of the transporters of the hormone thyroxine and the lipocalin retinol-binding protein (RBP), the specific carrier of the vitamin, are known to form, under physiological conditions, a macromolecular complex that is believed to play an important physiological role: prevention of glomerular filtration of the low molecular weight RBP in the kidneys. The physiological significance of complex formation is discussed first, followed by a brief description of the three-dimensional structure of the two participating proteins. The two X-ray models of the complex available are subsequently discussed and compared and finally the non-crystallographic evidence that supports these models is reviewed.

Section snippets

The complex: physiological role

Retinol transport in the plasma of vertebrates from the liver, which is the body’s major storage organ, to the peripheral tissues takes place with the vitamin bound to a single specific protein: the lipocalin retinol-binding protein [1] (RBP, see previous review). RBP circulates in plasma forming a macromolecular complex with another transport protein, the carrier of thyroxine transthyretin (TTR), formerly called prealbumin (for a comprehensive review see [2]). Both apo and holo RBP can form

Structure of the two members of the protein complex

The three-dimensional structure of human [34], [35], [36] and bovine [37] holo and apo RBP as well as the higher resolution structure of porcine RBP [38] have been extensively described (see also previous review). The wild type [39], [40], [41] and several mutants of human TTR [42], [43], [44] and of complexes of the wild type with pharmacologically important compounds [45], [46], [47] as well as chicken TTR [48] have been the subject of very detailed X-ray structural studies. The two members

Crystal structures of the complex

Two models of the TTR-RBP complex have been determined from X-ray diffraction data which extended in both cases to moderate resolution (3.1 and 3.2 Å respectively). The two structures determined are that of the chimeric complex human-TTR-chicken-RBP [50] and that of the homologous complex human-TTR-human-RBP [51]. For the chimeric complex it was found that the imposition of a stoichiometry of two RBP molecules per TTR tetramer was essential for successful crystallization [52]. An even higher

Experimental evidence that supports the X-ray models of the complex

The two X-ray models described above are in agreement with the results of a series of experimental studies of which we will give a brief account here.

It is known that the affinity of RBP for TTR is enhanced at high and reduced at low ionic strength [20] which is consistent with the participation of a hydrophobic area in the intermolecular contacts. Complex formation stabilizes the binding of retinol to RBP [57], [58] and substitution of this ligand can impair or even prevent the interaction of

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In the plasma, retinol is circulated as a tertiary complex with RBP4 and transthyretin (TTR). The complex formation depends on the association between retinol and RBP4 since retinol-free RBP4 (apo-RBP4) is less likely to bind to TTR [38–43]. Without binding to TTR, retinol-bound RBP4 (holo-RBP4) undergoes rapid elimination via glomerular filtration [44].
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ReviewThe transthyretin-retinol-binding protein complex

Abstract

Section snippets

The complex: physiological role

Structure of the two members of the protein complex

Crystal structures of the complex

Experimental evidence that supports the X-ray models of the complex

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Review
The transthyretin-retinol-binding protein complex