Janssen Onno E, Golcher Henriette M B, Grasberger Helmut, Saller Bernhard, Mann Klaus, Refetoff Samuel
Department of Medicine, University of Essen, D-45122 Essen, Germany.
J Clin Endocrinol Metab. 2002 Mar;87(3):1217-22. doi: 10.1210/jcem.87.3.8332.
T(4)-binding globulin (TBG) serves to maintain an important serum pool of thyroid hormones and to prevent their excessive loss in urine. TBG has also been implicated in the tissue distribution and targeted delivery of the hormones, the mechanisms of which remain unclear. By virtue of sequence homology, TBG belongs to the serine proteinase inhibitors superfamily of proteins that are characterized by a reactive site loop serving as a recognition site for serine proteinases. However, both TBG and another serpin with hormone transport function, corticosteroid-binding globulin, are noninhibitory. Cleavage of corticosteroid-binding globulin by human leukocyte elastase results in the reduction of its hormone-binding affinity and capacity. In this communication we confirm previous observations that TBG is also cleaved by elastase and undergoes the characteristic conformational changes. In addition, contrary to a previous report, the present work demonstrates that the cleaved product has reduced T(4)-binding affinity and, as expected, increased heat stability. Additional fragmentation of the molecule results in the loss of the hormone-binding site that is in agreement with a recent in vivo observation of apparent consumption at sites of inflammation. These data suggest that TBG may play a role in the targeted delivery of thyroid hormones to tissues rich in proteinases.
甲状腺素结合球蛋白（TBG）有助于维持甲状腺激素的重要血清池，并防止其在尿液中过度流失。TBG还与激素的组织分布和靶向递送有关，但其机制尚不清楚。由于序列同源性，TBG属于丝氨酸蛋白酶抑制剂超家族蛋白质，其特征是具有一个反应位点环，作为丝氨酸蛋白酶的识别位点。然而，TBG和另一种具有激素转运功能的丝氨酸蛋白酶抑制剂——皮质类固醇结合球蛋白均无抑制作用。人白细胞弹性蛋白酶对皮质类固醇结合球蛋白的切割会导致其激素结合亲和力和能力降低。在本通讯中，我们证实了之前的观察结果，即TBG也会被弹性蛋白酶切割并发生特征性的构象变化。此外，与之前的一份报告相反，目前的研究表明，切割产物的T4结合亲和力降低，并且正如预期的那样，热稳定性增加。分子的进一步断裂会导致激素结合位点的丧失，这与最近在体内观察到的炎症部位明显消耗的现象一致。这些数据表明，TBG可能在将甲状腺激素靶向递送至富含蛋白酶的组织中发挥作用。
