Molecular recognition of thyroglobulin by sortilin

Sortilin is a ubiquitous membrane receptor mediating protein trafficking along different cellular routes. In the thyroid gland, sortilin was proposed as a post-endocytic receptor of the thyroid hormone precursor, thyroglobulin (TG). It was reported that sortilin preferably shuttles iodinated TG to the lysosome, thereby facilitating the proteolytic release of thyroid hormones. However, the molecular details of this interaction are unknown. In this work, using an integrative approach, we reveal the structural basis of human TG recognition by sortilin. We found that sortilin interacts with a TG C-terminal peptide, which is more exposed in the monomeric TG than in its commonly found dimeric form. Unlike previously hypothesised, we suggest that the TG iodination state does not affect interaction with sortilin, which could act as a scavenger for degraded TG, as proposed for other cargoes. By comparing the mode of binding of TG and other known sortilin partners, we then derived a consensus ligand recognition motif. Overall, this study broadens understanding on the role of sortilin in TG trafficking and provides insight into general signatures for sortilin cargoes in other tissues.