A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Thyroglobulin (Tg) is a large protein precursor essential for thyroid hormone synthesis, storage, and release in vertebrates.
• Alterations in Tg structure and localization are linked to thyroid disorders, including autoimmune thyroid diseases and congenital hypothyroidism.
• The role of post-translational modifications (PTMs) in Tg function, thyroid homeostasis, and pathogenesis remains largely unknown.

Purpose of the Study:

• To provide an overview of recent cryo-electron microscopy (cryo-EM) models of Tg.
• To construct a three-dimensional map of known PTMs in Tg.
• To investigate the potential implications of PTMs in thyroid hormone synthesis, cellular interactions, and disease pathogenesis.

Main Methods:

• Review of existing electron cryo-microscopy (cryo-EM) data for thyroglobulin (Tg).
• Proteomic analyses to identify novel PTMs in Tg.
• Three-dimensional mapping of identified PTMs onto Tg structural models.

Main Results:

• Recent cryo-EM studies have revealed the structure of Tg in different states.
• New PTMs of Tg have been identified through proteomic analyses.
• Mapping PTMs suggests their involvement in hormonogenesis, cellular interactions, colloid cross-linking, and hormone release.
• Several PTMs are located in immunogenic regions and overlap with pathogenic mutations, indicating a link to thyroid disorders.

Conclusions:

• Post-translational modifications (PTMs) of thyroglobulin (Tg) play a significant role in thyroid function and homeostasis.
• PTMs may be implicated in the pathogenesis of thyroid diseases through interactions with immunogenic regions and mutations.
• An integrative approach combining multi-omics data with structural and functional Tg information is needed for targeted therapeutic strategies.