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 effe cts, to the multimerization of thyroglobulin (TG), the prothyroid hormone, Although hormone synthesis is a continuous process; the amount of Tg multim ers is relatively constant. Here, we investigated the role of two molecular chaperones, protein disulfide isomerase (PDI) and immunoglobulin heavy cha in-binding protein (BiP), present in the follicular lumen, on the multimeri zation process due to oxidation using both native Tg and its N-terminal dom ain (NTD), In vitro, PDI decreased multimerization of Tg and even suppresse d the formation of NTD multimers, Under the same conditions, BiP was able t o bind to Tg and NTD multimers but did not affect the process of multimeriz ation, Associating BiP with PDI did not enhance the ability of PDL to limit the formation of multimers produced by oxidation, However, when BiP and PD I were reacted together with the multimeric forms and for a longer time (48 h), BiP greatly increased the efficiency of PDI, Accordingly, these two mo lecular chaperones probably act sequentially on the reduction of the interm olecular disulfide bridges. In the thyroid, a similar process may also be e ffective 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, fur thermore, take part in the control of multimerization and aggregation of pr oteins formed by oxidation.