Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein.

The process of thyroid hormone synthesis, which occurs in the lumen of the thyroid follicles, results from an oxidative reaction leading, as side effects, to the multimerization of thyroglobulin (TG), the prothyroid hormone. Although hormone synthesis is a continuous process, the amount of Tg multimers is relatively constant. Here, we investigated the role of two molecular chaperones, protein disulfide isomerase (PDI) and immunoglobulin heavy chain-binding protein (BiP), present in the follicular lumen, on the multimerization process due to oxidation using both native Tg and its N-terminal domain (NTD). In vitro, PDI decreased multimerization of Tg and even suppressed the formation of NTD multimers. Under the same conditions, BiP was able to bind to Tg and NTD multimers but did not affect the process of multimerization. Associating BiP with PDI did not enhance the ability of PDI to limit the formation of multimers produced by oxidation. However, when BiP and PDI were reacted together with the multimeric forms and for a longer time (48 h), BiP greatly increased the efficiency of PDI. Accordingly, these two molecular chaperones probably act sequentially on the reduction of the intermolecular disulfide bridges. In the thyroid, a similar process may also be effective and participate in limiting the amount of Tg multimers present in the colloid. These results suggest that extracellular molecular chaperones play a similar role to that occurring in the endoplasmic reticulum and, furthermore, take part in the control of multimerization and aggregation of proteins formed by oxidation.