Structure of Human Thyroglobulin

Thyroid hormones T3 and T4 play a crucial role in the regulation of vertebrate metabolism. The thyroglobulin (Tg) protein is key to thyroid hormone synthesis, and its structure is conserved among vertebrates. TgG is delivered through the secretory pathway to the lumen of the thyroid gland, where it is iodinated at specific tyrosine sites to form mono- or di-iodotyrosine, which combine to produce T3 and T4, respectively. The formation of these hormones depends on the precise 3D structure of thyroglobulin, which has remained unknown despite decades of research on this protein. Here, we present the cryo-electron microscopy structure of human thyroglobulin, to a global resolution of 3.2 Å. Our results offer structural insight into thyroid hormonogenesis and provide a framework to understand hundreds of clinically relevant mutations. The structure of hTg contributes to a better understanding and potentially improved treatment of thyroid hypothyroidism, thyroid cancer and other Tg disorders.