Article Publish Status: FREE
Abstract Title:

Allosteric modulation of hormone release from thyroxine and corticosteroid-binding globulins.

Abstract Source:

J Biol Chem. 2011 May 6 ;286(18):16163-73. Epub 2011 Feb 16. PMID: 21325280

Abstract Author(s):

Xiaoqiang Qi, François Loiseau, Wee Lee Chan, Yahui Yan, Zhenquan Wei, Lech-Gustav Milroy, Rebecca M Myers, Steven V Ley, Randy J Read, Robin W Carrell, Aiwu Zhou

Article Affiliation:

Department of Biochemistry, Nanjing University, Nanjing, China.

Abstract:

The release of hormones from thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG) is regulated by movement of the reactive center loop in and out of theβ-sheet A of the molecule. To investigate how these changes are transmitted to the hormone-binding site, we developed a sensitive assay using a synthesized thyroxine fluorophore and solved the crystal structures of reactive loop cleaved TBG together with its complexes with thyroxine, the thyroxinefluorophores, furosemide, and mefenamic acid. Cleavage of the reactive loop results in its complete insertion into the β-sheet A and a substantial but incomplete decrease in binding affinity in both TBG and CBG. We show here that the direct interaction between residue Thr(342) of the reactive loopand Tyr(241) of the hormone binding site contributes to thyroxine binding and release following reactive loop insertion. However, a much larger effect occurs allosterically due to stretching of the connecting loop to the top of the D helix (hD), as confirmed in TBG with shortening of the loop by three residues, making it insensitive to the S-to-R transition. The transmission of the changes in the hD loop to the binding pocket is seen to involve coherent movements in the s2/3B loop linked to the hD loop by Lys(243), which is, in turn, linked to the s4/5B loop, flanking the thyroxine-binding site, by Arg(378). Overall, the coordinated movements of the reactive loop, hD, and the hormone binding site allow the allosteric regulation of hormone release, as with the modulation demonstrated here in response to changes in temperature.

Study Type : In Vitro Study
Additional Links
Problem Substances : Thyroxine : CK(146) : AC(24)

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