Structural mechanism for the carriage and release of thyroxine in the blood
Structural mechanism for the carriage and release of thyroxine in the blood
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DOI：
10.1073/pnas.0604080103
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发表时间：
2006-09-05
影响因子：
11.1
通讯作者：
Carrell, Robin W.
中科院分区：
文献类型：
--
作者：
Zhou, Aiwu;Wei, Zhenquan;Carrell, Robin W.
在健康和疾病中最直接控制组织活动的激素由蛋白酶抑制剂丝氨酸蛋白酶抑制剂家族的两个非抑制性成员甲状腺素结合球蛋白（TBG）和皮质类固醇结合球蛋白递送。TBG与四碘甲状腺素结合的结构，在2.8埃下解出，显示了甲状腺素如何被携带在分子的表面口袋中。TBG和皮质类固醇结合球蛋白中与激素结合丧失相关的突变证实了这个意想不到的结合位点。TBG与其他丝氨酸蛋白酶抑制剂的显著不同之处在于其主要β-折叠的上半部分完全打开，因此其反应中心肽环可以容易地移入和移出折叠，以平衡甲状腺素的结合和释放。环的进入引发构象变化，结合口袋的收缩和结合的甲状腺素的释放。这种变化的可逆性是由于TBG反应环中独特存在的脯氨酸，它阻碍了其他丝氨酸蛋白酶抑制剂中发生的完全和不可逆的环进入。因此，TBG已经调整了丝氨酸蛋白酶抑制剂抑制机制，以提供从高亲和力到低亲和力形式的可逆触发器转变。这种构象机制的复杂性和容易触发强烈表明，TBG已经发展到允许调节和靶向递送甲状腺素到组织。
The hormones that most directly control tissue activities in health and disease are delivered by two noninhibitory members of the serpin family of protease inhibitors, thyroxine-binding globulin (TBG) and corticosteroid-binding globulin. The structure of TBG bound to tetra-iodo thyroxine, solved here at 2.8 angstrom, shows how the thyroxine is carried in a surface pocket on the molecule. This unexpected binding site is confirmed by mutations associated with a loss of hormone binding in both TBG and also homologously in corticosteroid-binding globulin. TBG strikingly differs from other serpins in having the upper half of its main beta-sheet fully opened, so its reactive center peptide loop can readily move in and out of the sheet to give an equilibrated binding and release of thyroxine. The entry of the loop triggers a conformational change, with a linked contraction of the binding pocket and release of the bound thyroxine. The ready reversibility of this change is due to the unique presence in the reactive loop of TBG of a proline that impedes the full and irreversible entry of the loop that occurs in other serpins. Thus, TBG has adapted the serpin inhibitory mechanism to give a reversible flip-flop transition, from a high-affinity to a low-affinity form. The complexity and ready triggering of this conformational mechanism strongly indicates that TBG has evolved to allow a modulated and targeted delivery of thyroxine to the tissues.