The structure of human thyroglobulin.

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.

journal_name

Nature

journal_title

Nature

authors

Coscia F,Taler-Verčič A,Chang VT,Sinn L,O'Reilly FJ,Izoré T,Renko M,Berger I,Rappsilber J,Turk D,Löwe J

doi

10.1038/s41586-020-1995-4

subject

Has Abstract

pub_date

2020-02-01 00:00:00

pages

627-630

issue

7796

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-020-1995-4

journal_volume

578

pub_type

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