Dataset Information

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 A 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.

SUBMITTER: Petitpas I

PROVIDER: S-EPMC164465 | biostudies-literature | 2003 May

REPOSITORIES: biostudies-literature

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Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia.

Petitpas Isabelle I Petersen Charles E CE Ha Chung-Eun CE Bhattacharya Ananyo A AA Zunszain Patricia A PA Ghuman Jamie J Bhagavan Nadhipuram V NV Curry Stephen S

Proceedings of the National Academy of Sciences of the United States of America 20030512 11

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 ...[more]

PMID: 12743361

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Project description:A series of human autoantibodies against thyroglobulin (Tg) which exhibit different specificities for iodothyronines were studied. The ability of a thyroxine (T4)-containing peptide (T4P) isolated from human thyroglobulin (Tg) to displace [125I]T3 from human T3-specific autoantisera was 11-50 times greater than that of T4 alone. These antisera therefore strongly recognize amino acids adjacent to T4 in the Tg structure. This was confirmed when a Tg preparation (Tg[0.05]) containing an average of only 0.05 of a T4 residue/molecule and much less T3 had good cross-reactivities with these antisera. Cross-reactivities of other Tg preparations with different T4 contents increased only slowly with increase of T4 content up to a mean of 6.6 residues/molecule and were not proportional to T3 content. In contrast, cross-reactivities with a human T4-specific autoantiserum were strongly dependent on T4 content. Tg[0.05] was 500 times less reactive than T4P and 615 times less than T4. Cross-reactivities rose rapidly as the T4 content of Tg preparations increased from a mean of 0.05 to approx. 1-2 residues/molecule. Thyroxine is therefore a dominant feature of the antigenic site for this antiserum. There was little further increase in cross-reactivities for those Tg preparations containing up to an average of 6.6 residues T4 per molecule, confirming previous conclusions that all T4-containing sites are not immunologically identical and that autoantibodies exhibit a preference for particular sites on Tg. Similar conclusions were reached for a non-specific iodothyronine-binding antiserum. These results indicate that iodothyronine specificity in human autoantisera is not necessarily determined by the iodothyronine present in the immunogenic area, but by the precise site selected by the immune response. T4- or non-specific antibodies have thyroxine as a dominant feature of the antigenic site. T3- specific antibodies have the thyroxine residue as a peripheral feature of the binding site, and it is not necessary to postulate that T3 was part of the immunogen or is required in the epitope. These antisera may have value in mapping the hormonogenic regions in Tg from human and other species.

Dataset Information

Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia.

Publications

Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia.

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