2. Academic Validation
  3. The structure of human thyroglobulin

The structure of human thyroglobulin

  • Nature. 2020 Feb;578(7796):627-630. doi: 10.1038/s41586-020-1995-4.
Francesca Coscia 1,  Ajda Taler-Verčič 2 3,  Veronica T Chang 1,  Ludwig Sinn 4,  Francis J O'Reilly 4,  Thierry Izoré 1,  Miha Renko 2,  Imre Berger 5,  Juri Rappsilber 4 6,  Dušan Turk 7 8,  Jan Löwe 9
Affiliations

Affiliations

  • 1 MRC Laboratory of Molecular Biology, Cambridge, UK.
  • 2 Jožef Stefan Institute, Ljubljana, Slovenia.
  • 3 Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia.
  • 4 Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
  • 5 Max Planck Bristol Centre for Minimal Biology, University of Bristol, Bristol, UK.
  • 6 Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
  • 7 Jožef Stefan Institute, Ljubljana, Slovenia. dusan.turk@ijs.si.
  • 8 Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia. dusan.turk@ijs.si.
  • 9 MRC Laboratory of Molecular Biology, Cambridge, UK. jyl@mrc-lmb.cam.ac.uk.
PMID: 32025030 DOI: 10.1038/s41586-020-1995-4
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.

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