Mutations in a specific human serum albumin thyroxine binding site define the structural basis of familial dysalbuminemic hyperthyroxinemia

被引:55
作者
Petersen, CE [1 ]
Ha, CE [1 ]
Jameson, DM [1 ]
Bhagavan, NV [1 ]
机构
[1] UNIV HAWAII MANOA,DEPT BIOCHEM & BIOPHYS,HONOLULU,HI 96822
关键词
D O I
10.1074/jbc.271.32.19110
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The familiar dysalbuminemic hyperthyroxinemia (FDR) phenotype results hom a natural human serum albumin (HSA) mutant with histidine instead of arginine at amino acid position 218. This mutation results in an enhanced affinity for thyroxine, Site-directed mutagenesis and a yeast protein expression system were used to synthesize wild type BSA and FDN HSA as well as several other HSA mutants. Studies oil the binding of thyroxine to these HSA species using equilibrium dialysis and quenching of tryptophan 214 fluorescence suggest that the FDH mutation affects a single thyroxine binding site located in the 2A subdomain of HSA. Site-directed mutagenesis of HSA and thyroxine analogs mere used to obtain information about the mechanism of thyroxine binding to both wild type and FDH HSA. These studies suggest that the guanidino group of arginine at,amino acid position 218 in wild type RSA is involved in an unfavorable binding interaction with the amino group of thyroxine, whereas histidine at amino acid position 218 in FDR HSA is involved in a favorable binding interaction with thyroxine. Neither arginine at amino acid position 222 nor tryptophan at amino acid position 214 appears to favorably influence the binding of thyroxine to wild type HSA.
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页码:19110 / 19117
页数:8
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