The structure of human thyroglobulin

Francesca Coscia, Ajda Taler-Verčič, Veronica T. Chang, Ludwig Sinn, Francis J. O’Reilly, Thierry Izoré, Miha Renko, Imre Berger, Juri Rappsilber, Dušan Turk () and Jan Löwe ()
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Francesca Coscia: MRC Laboratory of Molecular Biology
Ajda Taler-Verčič: Jožef Stefan Institute
Veronica T. Chang: MRC Laboratory of Molecular Biology
Ludwig Sinn: Technische Universität Berlin
Francis J. O’Reilly: Technische Universität Berlin
Thierry Izoré: MRC Laboratory of Molecular Biology
Miha Renko: Jožef Stefan Institute
Imre Berger: University of Bristol
Juri Rappsilber: Technische Universität Berlin
Dušan Turk: Jožef Stefan Institute
Jan Löwe: MRC Laboratory of Molecular Biology

Nature, 2020, vol. 578, issue 7796, 627-630

Abstract: Abstract Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates1,2. Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis3. Tyrosine proximity within TG is thought to enable the coupling reaction but hormonogenic tyrosines have not been clearly identified, and the lack of a three-dimensional structure of TG has prevented mechanistic understanding4. Here we present the structure of full-length human thyroglobulin at a resolution of approximately 3.5 Å, determined by cryo-electron microscopy. We identified all of the hormonogenic tyrosine pairs in the structure, and verified them using site-directed mutagenesis and in vitro hormone-production assays using human TG expressed in HEK293T cells. Our analysis revealed that the proximity, flexibility and solvent exposure of the tyrosines are the key characteristics of hormonogenic sites. We transferred the reaction sites from TG to an engineered tyrosine donor–acceptor pair in the unrelated bacterial maltose-binding protein (MBP), which yielded hormone production with an efficiency comparable to that of TG. Our study provides a framework to further understand the production and regulation of thyroid hormones.

Date: 2020
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DOI: 10.1038/s41586-020-1995-4

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