6scj
The structure of human thyroglobulin
Structural highlights
DiseaseTHYG_HUMAN Familial thyroid dyshormonogenesis. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionTHYG_HUMAN Precursor of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3). Publication Abstract from PubMedThyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates(1,2). Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis(3). 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 understanding(4). Here we present the structure of full-length human thyroglobulin at a resolution of approximately 3.5 A, 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. The structure of human thyroglobulin.,Coscia F, Taler-Vercic A, Chang VT, Sinn L, O'Reilly FJ, Izore T, Renko M, Berger I, Rappsilber J, Turk D, Lowe J Nature. 2020 Feb 5. pii: 10.1038/s41586-020-1995-4. doi:, 10.1038/s41586-020-1995-4. PMID:32025030[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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