Structural basis of albumin–thyroxine interactions and familial dysalbuminemic hyperthyroxinemia

Abstract

Human serum albumin (HSA) is the major protein component of blood plasma and serves as a transporter for thyroxine and other hydrophobic compounds such as fatty acids and bilirubin. We report here a structural characterization of HSA-thyroxine interactions. Using crystallographic analyses we have identified four binding sites for thyroxine on HSA distributed in subdomains IIA, IIIA, and IIIB. Mutation of residue R218 within subdomain IIA greatly enhances the affinity for thyroxine and causes the elevated serum thyroxine levels associated with familial dysalbuminemic hyperthyroxinemia (FDH). Structural analysis of two FDH mutants of HSA (R218H and R218P) shows that this effect arises because substitution of R218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. We have also found that, although fatty acid binding competes with thyroxine at all four sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 Å from R218. These structural observations are consistent with binding data showing that HSA retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.

Altered plasma albumin characteristics and lymphocyte populations in gastrointestinal cancer patients: Detection using modified fluorescence responses

“…Such shifts would be in agreement with the observations of Ryder (2006, 2007) that albumin molecules are known to contain different binding sites (i.e., classes) for various probes. As Petitpas et al (2001bPetitpas et al ( , 2003 noted, albumin normally carries a variety of endogenous ligands like nonesterified fatty acids, bilirubin, and thyroxine; however, this protein can also bind an impressive array of drug molecules, including warfarin, ibuprofen, and indomethacin, as well as their metabolites (Petitpas et al, 2001a). It seems very likely that patients in the groups in the present study had ingested painkillers (both prescribed and retail) during the course of their disease; thus, a presence of these drugs/ metabolites on their albumin could have contributed to the noted shifts in ABM fluorescence/K a values.…”

The extraordinary ligand binding properties of human serum albumin

“…His and Arg218 ! Pro mutations have been found to be responsible for the clinical condition of familial dysalbuminemic hyperthyroxinemia (28,72) and the Leu66!Pro mutation is the reason for familial dysalbuminemic hypertriiodothyroninemia (73).…”

Translational and Rotational Motions of Albumin Sensed by a Non-Covalent Associated Porphyrin Under Physiological and Acidic Conditions: A Fluorescence Correlation Spectroscopy and Time Resolved Anisotropy Study

“…Hence, it is important to investigate how and to which extent it influences the photosensitized reactions. Conversely, upon binding, ligands can induce structural modifications in the proteins [6][7][8].…”