How sortilin senses thyroglobulin along its pathway to thyroid hormone release - Human Technopole

Human Technopole researchers have identified the molecular mechanisms by which the membrane receptor sortilin binds thyroglobulin along its pathway to the release of thyroid hormones within the thyroid gland. The results of the research were published in Nature Communications and highlight that sortilin senses thyroglobulin via a short flexible “tag” which appears to be a common motif for the recognition of other partner proteins throughout our body.

The thyroid gland regulates the body’s metabolism, growth, and energy by producing thyroid hormones. These hormones are made from iodine, an essential element, and are synthesised within the thyroid gland from a large protein precursor called thyroglobulin. However, synthesis is just the beginning: these hormones undergo a complex pathway before they can enter the bloodstream and exert their function on distant organs.

In the thyroid, cells organise into hollow spheres called follicles, which secrete thyroglobulin into a central compartment (the lumen). Here, the protein is iodinated (i.e., coupled with iodine) and makes thyroid hormones on its surface. The iodinated thyroglobulin is then taken back into the thyroid cells through a process called endocytosis and eventually broken down in acidic cellular organelles – the lysosomes – to produce the active thyroid hormones that are subsequently released into the bloodstream.

A key molecular player in this re-uptake is sortilin, a well-known membrane receptor known to help the traffic of several protein “cargoes” in cells. Sortilin has been linked to numerous biological processes and diseases in other organs (e.g., cancer, Alzheimer’s, heart disease), but its exact role in thyroglobulin recognition has remained unclear. Earlier studies suggested sortilin preferably binds highly iodinated thyroglobulin, implying that iodine plays a role in recognition.

The Group of Francesca Coscia at Human Technopole has shown that iodination is not required for binding. Instead, sortilin preferably binds to thyroglobulin when it is in a monomeric form, rather than its commonly found dimeric state.

Using a combination of advanced methods such as cryo-electron microscopy, biophysics, and mass spectrometry, the Group found that sortilin recognizes a flexible peptide at the C-terminal end of thyroglobulin. The complex with the whole thyroglobulin would be sterically impaired when two thyroglobulin subunits associate (in the common dimeric form), but it is allowed if only one subunit of thyroglobulin is present in the complex (the monomer). Importantly, these data are further confirmed by thyroglobulin uptake studies in thyroid cell lines.

How does thyroglobulin go from dimer to monomer in the thyroid? The researchers suggest that proteolytic enzymes, such as cathepsins, may break down thyroglobulin outside the cells, loosening its structure and exposing the binding site. This process would enable sortilin to bind and internalise the protein along its route to hormone release. Using for the first time advanced imaging methods at the atomic scale, the study highlights the importance of further investigations in this direction, as the monomeric form of thyroglobulin was found in the past in thyroids, but its function and formation have been elusive.

Sortilin also interacts with many other proteins involved in diverse functions in other organs. Does it recognize its other cargoes via the same mechanism as thyroglobulin? Because only a few structures are available of sortilin in complex with its partners, the Group used a computational pipeline based on artificial intelligence (AlphaFold) to address this question. The results highlight that in several simulated cargo-sortilin structures, a similar (orientation-independent) unstructured peptide motif of the cargo is docked into the same sortilin pocket where the C-terminal thyroglobulin fragment is bound.

Taken together, this work suggests a new hypothesis of how sortilin can select cargoes through flexible motifs that can become exposed during protein processing. This finding advances our understanding of how thyroid hormone precursors are trafficked and may reshape how scientists think about thyroid hormone regulation.

More broadly, the results contribute to a growing picture of the participation of sortilin in its trafficking pathways and may inform future studies exploring its interactions with diverse targets or its relevance in disease mechanisms.

Boniardi, I., Tanzi, G., Di Ianni, A. et al. Molecular recognition of thyroglobulin by sortilin. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68658-z