Mutants and molecular dockings reveal that the primary L-thyroxine binding site in human serum albumin is not the one which can cause familial dysalbuminemic hyperthyroxinemia

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

“…High-affinity binding of T4 to 32 other genetic variants of HSA has been examined by equilibrium dialysis, and the studies revealed two additional cases of increased binding and eight examples of decreased binding ( 4 ). Almost all of the modified bindings were caused by mutations in domain III, mainly in subdomain IIIB (Figure 2 ).…”

“…Other forces, which stabilize binding are hydrogen bond interactions between the phenolic hydroxyl of T4 (Figure 1 ) and the side chains of Tyr150 and Arg257, a salt-bridge interaction between the carboxyl moiety and Lys199 and perhaps also Lys195, and the iodine atoms making hydrophilic contacts with side chains and main-chain carbonyl oxygens within the site ( 6 ) (Figure 4 ). In addition, molecular modeling performed on relaxed protein structure shows a strong interaction between the amino group of T4 and Glu292 ( 4 ). T4 binds to the site in a cisoid conformation with the amino-propionic acid and the outer phenolic ring both on the same side of the inner ring of the molecule ( 6 ) (Figure 4 ).…”

“…Among the three proteins, HSA is found in the highest concentration, namely 42 g/L (0.6 mM) ( 3 ). The protein has more binding sites for the hormones but with the lowest high-affinity constants, i.e., in the order of 10 5 –10 6 M −1 ( 1 , 4 ), which results in binding of ca. 5% of T4 and ca.…”

“…The function can also be changed by genetic modification of the protein. In the case of especially T4, but also of T3, several genetic variants show altered binding, the most well-known of these are mutation of Arg218 or Arg222 in the case of T4 resulting in familial dysalbuminemic hyperthyroxinemia (FDH-T4) (OMIM #615999) and Lys66 in the case of T3 leading to familial dysalbuminemic hypertriiodothyroninemia (FDH-T3) ( 4 ). All the FDH-T4 and FDH-T3 patients so far described are heterozygous for the causative mutation.…”

Structure-related interactions of brominated and organophosphate flame retardants and degradation products with thyroxine and human thyroid hormone transport proteins in vitro

“…Albumin is a single polypeptide chain that forms three alpha-helical domains, each containing two subdomains (Figure 1-3) (Kragh-Hansen et al, 2016;Yang et al, 2014). There are four main binding sites for T4 across the protein, and hydrogen bonds are the main interactions that occur between ALB and T4, with each binding site resulting in a different ligand orientation (Tarhoni et al, 2008).…”