Structural changes in transthyretin produced by the Ile 84 Ser mutation which result in decreased affinity for retinol-binding protein

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Abstract
The X-ray crystal structure of the transthyretin variant Ile 84 Ser has been determined to 1.7Å resolution. The functional form of normal transthyretin is a tetramer, having a cylindrical cavity which binds thyroxine and an exterior binding site for the complex of retinol with retinol-binding protein. The naturally occurring amyloidogenic variant Ile 84 Ser has reduced affinity for retinol-binding protein. The results of this study show that the overall structural homology between the C-alpha atoms of the variant and normal protein is very high with differences mainly in the loop regions, in the vicinity of the substitution, and the ligand binding areas. The known functional differences for the variant (ligand-binding) are correlated with the structural changes observed in the region of the ligand-binding site. The substitution at position 84 results in changes in the shape of the putative site for complexation with retinol binding protein. The substitution site occurs at the interface between two tetramers which are nearest neighbors in the crystal in the direction parallel to the a axis of the unit cell. The variant tetraners move closer together resulting in a hydrogen bond across the interface which does not form in the normal protein. This dominant packing interface may be significant in amyloidogenesis.