Mechanism of TGF beta receptor inhibition by FKBP12
Mechanism of TGF beta receptor inhibition by FKBP12
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DOI：
10.1093/emboj/16.13.3866
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发表时间：
1997-07-01
期刊：
影响因子：
11.4
通讯作者：
Massague, J
中科院分区：
文献类型：
--
作者：
Chen, YG;Liu, F;Massague, J
转化生长因子β（TGF β）信号传导需要通过T β R-II磷酸化I型受体T β R-I。虽然TGF β促进T β R-I与T β R-II的结合，但这些受体组分彼此具有亲和力，这可导致其配体非依赖性活化。亲免素FKBP 12与T β R-I结合并抑制其信号传导功能。我们研究了这种效应的机制和功能意义。FKBP 12与T β R-I的结合涉及FKBP 12的雷帕霉素/Leu-Pro结合口袋和位于T β R-I中活化磷酸化位点旁边的Leu-Pro序列。FKBP 12或T β R-I结合位点的突变消除了这些蛋白质之间的相互作用，导致在不存在添加配体的情况下受体活化。FKBP 12不抑制T β R-I与T β R-II的结合，但抑制T β R-II对T β R-I的磷酸化。阻断FKBP 12与T β R-I结合的雷帕霉素逆转了FKBP 12对T β R-I磷酸化的抑制作用。通过阻止在不存在配体的情况下形成的TGF β受体复合物的活化，FKBP 12可以提供针对由T β R-I和T β R-II相互作用的先天倾向导致的信号泄漏的保护。
Transforming growth factor-beta (TGF beta) signaling requires phosphorylation of the type I receptor T beta R-I by T beta R-II. Although TGF beta promotes the association of T beta R-I with T beta R-II, these receptor components have affinity for each other which can lead to their ligand-independent activation. The immunophilin FKBP12 binds to T beta R-I and inhibits its signaling function. We investigated the mechanism and functional significance of this effect. FKBP12 binding to T beta R-I involves the rapamycin/Leu-Pro binding pocket of FKBP12 and a Leu-Pro sequence located next to the activating phosphorylation sites in T beta R-I. Mutations in the binding sites of FKBP12 or T beta R-I abolish the interaction between these proteins, leading to receptor activation in the absence of added ligand. FKBP12 does not inhibit T beta R-I association with T beta R-II, but inhibits T beta R-I phosphorylation by T beta R-II. Rapamycin, which blocks FKBP12 binding to T beta R-I, reverses the inhibitory effect of FKBP12 on T beta R-I phosphorylation. By impeding the activation of TGF beta receptor complexes formed in the absence of ligand, FKBP12 may provide a safeguard against leaky signaling resulting from the innate tendency of T beta R-I and T beta R-II to interact with each other.