University of Cambridge > > Seminars at the Department of Biochemistry > Cryo-EM Forum: The structure of human thyroglobulin

Cryo-EM Forum: The structure of human thyroglobulin

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Thyroglobulin is the protein 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 coupling of pairs of tyrosines and is completed by TG proteolysis. 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. Here we present the de novo structure of full-length human thyroglobulin at ~3.5 Å resolution determined by electron cryomicroscopy (cryo-EM). We identified all hormonogenic tyrosine pairs in the structure and verified them via site-directed mutagenesis and in vitro hormone production assays using human TG expressed in HEK cells. Analysis revealed that proximity, flexibility and solvent exposure of the tyrosines are the key characteristics of hormonogenic sites. To support the validity of our insights, we transferred the reaction site properties from TG to an engineered tyrosine donor-acceptor pair in the unrelated bacterial maltose binding protein (MBP). This yielded hormone production with efficiency comparable to TG. This structure provides an essential framework to further understand the production and regulation of thyroid hormones.

This talk is part of the Seminars at the Department of Biochemistry series.

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