The structure of human thyroglobulin

Francesca Coscia, Ajda Taler-Vercic, Veronica Chang, Ludwig Sinn, Francis O'Reilly, Thierry Izore, Miha Renko, Imre Berger, Juri Rappsilber, Dusan Turk*, Jan Lowe*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Pages (from-to)627-630
Number of pages19
JournalNature
Volume578
DOIs
Publication statusPublished - 5 Feb 2020

Keywords

  • Enzyme mechanisms
  • Endocrine system and metabolic diseases
  • Cryoelectron microscopy

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