Reciprocal mutagenesis between human alpha(L349, M528) and rainbow trout (M317, I496) estrogen receptor residues demonstrates their importance in ligand binding and gene expression at different temperatures

Molecular and Cellular Endocrinology
J B MatthewsT R Zacharewski

Abstract

Several fish proteins exhibit compromised function at temperatures outside of their normal physiological range. In this study, the effect of temperature on the ligand binding and the transactivation abilities of the rainbow trout estrogen receptor (rtER) and human estrogen receptor alpha (hER alpha) were examined. Saturation analysis and gene expression assays, using GST-ER and Gal4-ER fusion proteins consisting of the D, E and F domains of human (hER alpha def) and rainbow trout (rtERdef) receptors, show that GST-rtERdef E2 binding affinity and transactivation ability decrease with increasing temperature. A comparison of the amino acid sequence differences between their ligand binding pockets identified two conservative amino acid residue substitutions in rtER (M317, I496) and hER alpha (L349, M528). The effect of these substitutions on ligand binding and transactivation were examined by constructing reciprocal mutants, which effectively exchanged the binding pockets between rtER and hER alpha. The rtERdef M317L:I496M double mutant exhibited increased E2 binding affinity and transactivation ability at higher temperatures, and displayed hER alpha phenotypic behavior for the phytoestrogen, coumestrol. The hER alpha def L349M:M52...Continue Reading

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Citations

Dec 13, 2002·The Journal of Steroid Biochemistry and Molecular Biology·J B MatthewsT R Zacharewski
Aug 28, 2002·Congenital Anomalies·Taisen IguchiHideo Kato
Nov 19, 2014·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·A R BrownC R Tyler
Aug 19, 2008·Toxicology and Applied Pharmacology·José-Manuel Molina-MolinaPatrick Balaguer
Aug 16, 2005·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Christel M OlsenKnut-Erik Tollefsen

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