Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone.
Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone.
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DOI：
10.1016/j.celrep.2021.109317
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发表时间：
2021-07-06
期刊：
影响因子：
8.8
通讯作者：
Prodromou C
中科院分区：
文献类型：
--
作者：
Pal M;Muñoz-Hernandez H;Bjorklund D;Zhou L;Degliesposti G;Skehel JM;Hesketh EL;Thompson RF;Pearl LH;Llorca O;Prodromou C
R2 TP（RUVBL 1-RUVBL 2-RPAP 3-PIH 1D 1）复合物与热休克蛋白90（HSP 90）协同作用，作为蛋白质复合物的组装和稳定性的伴侣，所述蛋白质复合物包括RNA聚合酶、小核核糖核蛋白颗粒（snRNP）和磷脂酰肌醇3-激酶（PI 3 K）样激酶（PIKK）如TOR和SMG 1。PIKK的稳定依赖于TELO 2、TTI 1和TTI 2（TTT）的额外复合物，其结构和功能知之甚少。人R2 TP-TTT复合物的冷冻电子显微镜（cryo-EM）结构以及生物化学实验揭示了TOR募集至R2 TP-TTT分子伴侣的机制。HEAT-重复TTT复合物结合TOR的激酶结构域，而不阻断其活性，并将TOR递送至R2 TP分子伴侣。此外，TTT通过抑制RUVBL 1-RUVBL 2 ATP酶活性以及通过调节R2 TP的PIH 1D 1和RPAP 3组分的构象和相互作用来调节R2 TP伴侣。总之，我们的研究结果显示了TTT如何将TOR的募集与R2 TP结合起来，并调节该分子伴侣系统。TELO 2-TTI 1-TTI 2（TTT）与RUVBL 1-RUVBL 2（R2）形成直接复合物TTT与异源六聚体R2环中的两个连续DII结构域相互作用TTT抑制R2 ATP酶并拮抗RPAP 3/Tah 1 p-PIH 1D 1/Pih 1 p接合TTI 1-TTI 2结合mTOR的激酶区域但不抑制其催化活性报道了与RUVBL 1-RUVBL 2（R2）AAA+ ATP酶的异六聚体环结合的TELO 2-TTI 1-TTI 2（TTT）复合物的冷冻电镜结构，显示了TTI 1和TTI 2的HEAT重复序列与R2 DII结构域的直接相互作用。TTT结合抑制R2 ATP酶活性并促进mTOR募集。
The R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with heat shock protein 90 (HSP90), functions as a chaperone for the assembly and stability of protein complexes, including RNA polymerases, small nuclear ribonucleoprotein particles (snRNPs), and phosphatidylinositol 3-kinase (PI3K)-like kinases (PIKKs) such as TOR and SMG1. PIKK stabilization depends on an additional complex of TELO2, TTI1, and TTI2 (TTT), whose structure and function are poorly understood. The cryoelectron microscopy (cryo-EM) structure of the human R2TP-TTT complex, together with biochemical experiments, reveals the mechanism of TOR recruitment to the R2TP-TTT chaperone. The HEAT-repeat TTT complex binds the kinase domain of TOR, without blocking its activity, and delivers TOR to the R2TP chaperone. In addition, TTT regulates the R2TP chaperone by inhibiting RUVBL1-RUVBL2 ATPase activity and by modulating the conformation and interactions of the PIH1D1 and RPAP3 components of R2TP. Taken together, our results show how TTT couples the recruitment of TOR to R2TP with the regulation of this chaperone system. TELO2-TTI1-TTI2 (TTT) forms a direct complex with RUVBL1-RUVBL2 (R2) TTT interacts with two consecutive DII domains in the heterohexameric R2 ring TTT inhibits R2 ATPase and antagonizes RPAP3/Tah1p–PIH1D1/Pih1p engagement TTI1-TTI2 binds the kinase region of mTOR but does not inhibit its catalytic activity Pal et al. report the cryo-EM structure of the TELO2-TTI1-TTI2 (TTT) complex bound to a heterohexameric ring of the RUVBL1-RUVBL2 (R2) AAA+ ATPases, showing a direct interaction of the HEAT repeats of TTI1 and TTI2 with R2 DII domains. TTT binding inhibits R2 ATPase activity and facilitates mTOR recruitment.
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