Structural Basis of Albumin-Thyroxine Interactions and Familial Dysalbuminemic Hyperthyroxinemia

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 id...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-05, Vol.100 (11), p.6440-6445
Main Authors: Petitpas, Isabelle, Petersen, Charles E., Ha, Chung-Eun, Bhattacharya, Ananyo A., Zunszain, Patricia A., Ghuman, Jamie, Bhagavan, Nadhipuram V., Curry, Stephen
Format: Article
Language:English
Subjects:
Albumins - metabolism
Atoms
Binding Sites
Biological Sciences
Carboxylates
Cell division
Crystals
Fatty acids
Health savings accounts
Hormones
Humans
Hydrogen bonds
Hyperthyroxinemia - genetics
Hyperthyroxinemia - metabolism
Ligands
Models, Molecular
Molecular Structure
Molecules
Mutation
Myristates
Protein Binding
Proteins
Thyroxine - metabolism
X-Ray Diffraction
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1137188100