Proteomics

Dataset Information

0

The structure of human thyroglobulin


ABSTRACT: Thyroglobulin protein is the precursor of thyroid hormones, which are essential for growth, development and control of metabolism in vertebrates. Hormone synthesis from thyroglobulin (TG) occurs in the thyroid gland via the iodination and subsequent coupling of pairs of tyrosine amino acids, whose positions in TG have not been clearly identified. Tyrosine proximity within TG is thought to enable the coupling reactions but the lack of a three-dimensional structure of TG has prevented mechanistic understanding. Here we determined the structure of full-length human thyroglobulin at ~3.4 Å resolution by cryo-electron microscopy (cryo-EM). To enable perturbation experiments we expressed human TG in human HEK cells and showed it to be active in hormone production. We identified all hormogenic tyrosine pairs in the structure and verified them via site-directed mutagenesis and in vitro hormone production assays. Analysis revealed that proximity, flexibility and solvent exposure of the tyrosines are key characteristics of the hormogenic sites. To support the validity of our insights, we engineered the small bacterial protein MBP (maltose binding protein) to produce thyroid hormones with similar efficiency as TG. Finally, our study provides an essential framework to further understand the production and regulation of thyroid hormones, including in thyroid diseases.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ludwig Sinn  

LAB HEAD: Juri Rappsilber, PhD

PROVIDER: PXD014821 | Pride | 2020-02-06

REPOSITORIES: Pride

altmetric image

Publications


Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates<sup>1,2</sup>. Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis<sup>3</sup>. 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 struc  ...[more]

Similar Datasets

2022-02-24 | PXD018452 | Pride
2020-11-20 | PXD019427 | Pride
2022-02-17 | PXD029013 | Pride
2023-05-26 | GSE233457 | GEO
2021-12-06 | GSE183963 | GEO
2021-12-06 | GSE183962 | GEO
2021-12-06 | GSE183961 | GEO
2022-10-24 | GSE203084 | GEO
2022-10-24 | GSE201558 | GEO
2022-10-24 | GSE181256 | GEO