ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2020) 17 3.1 | DOI: 10.1530/ey.17.3.1


To read the full abstract: Nature. 2020;578:627–630.

In this extensive work, Coscia et al. determined the molecular architecture of the full-length human thyroglobulin (TG) at high resolution by cryo-electron microscopy and identified the four hormonogenic tyrosine residues which act either as mono- or di-iodotyrosine acceptor and donor sites (A-D) and allow the ultimate step of thyroid hormone synthesis – coupling of two di- or one mono- and one di-iodotyrosine to T4 and T3. The authors validated their structural results by extensive site-directed mutagenesis of human TG, analyzing the hormone synthetic capacity of the mutated TG proteins in vitro. Although distributed in three domains the four donor acceptor sites share structural key features: acceptor donor residues are located in proximity in an antiparallel way and structurally positioned to be solvent-exposed for iodination. Finally, the authors tested the hormone production efficiency of the characterized TG reaction sites outside of the TG structure by transferring them to a bacterial protein by maintaining structural properties of the residues as in the TG monomer. The hormone production of the engineered construct containing the human TG acceptor-donor residues is comparable to that of human TG.

This fundamental, elegant and extensive study resolves the molecular basis of thyroglobulin function conserved in many species. It was well established that tyrosines within the TG protein play a central role for thyroid hormone synthesis [1]. Further, it was known that tyrosine residues either act as mono- or di-iodotyrosine donor or acceptor sites. The TG monomer contains 66 tyrosines of which only 33 are iodinated after secretion into the follicular lumen. But only a few of these 33 tyrosines have been identified so far as acceptor site for coupling of two di- or one mono- and one di-iodotyrosine. In summary, the authors identified all functional sites of hormone synthesis as well as their structural properties. This work represents a milestone in thyroid physiology providing the full picture of TG structure and function and integrating and completing previous results of the last decades.

Reference:

1. Citterio CE, Targovnik HM, Arvan P. The role of thyroglobulin in thyroid hormonogenesis. Nat Rev Endocrinol. 2019;16:323–338.

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