The HSP90/R2TP Quaternary Chaperone Scaffolds Assembly of the TSC Complex.

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Biology Pub Date : 2024-10-26 DOI:10.1016/j.jmb.2024.168840

Claire Abéza, Philipp Busse, Ana C F Paiva, Marie-Eve Chagot, Justine Schneider, Marie-Cécile Robert, Franck Vandermoere, Christine Schaeffer, Bruno Charpentier, Pedro M F Sousa, Tiago M Bandeiras, Xavier Manival, Sarah Cianferani, Edouard Bertrand, Céline Verheggen

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引用次数: 0

Abstract

The R2TP chaperone is composed of the RUVBL1/RUVBL2 AAA+ ATPases and two adapter proteins, RPAP3 and PIH1D1. Together with HSP90, it functions in the assembly of macromolecular complexes that are often involved in cell proliferation. Here, proteomic experiments using the isolated PIH domain reveals additional R2TP partners, including the Tuberous Sclerosis Complex (TSC) and many transcriptional complexes. The TSC is a key regulator of mTORC1 and is composed of TSC1, TSC2 and TBC1D7. We show a direct interaction of TSC1 with the PIH phospho-binding domain of PIH1D1, which is, surprisingly, phosphorylation independent. Via the use of mutants and KO cell lines, we observe that TSC2 makes independent interactions with HSP90 and the TPR domains of RPAP3. Moreover, inactivation of PIH1D1 or the RUVBL1/2 ATPase activity inhibits the association of TSC1 with TSC2. Taken together, these data suggest a model in which the R2TP recruits TSC1 via PIH1D1 and TSC2 via RPAP3 and HSP90, and use the chaperone-like activities of RUVBL1/2 to stimulate their assembly.

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HSP90/R2TP四级伴侣支架了TSC复合体的组装。

R2TP 合子由 RUVBL1/RUVBL2 AAA+ ATP 酶和两个适配蛋白 RPAP3 和 PIH1D1 组成。它与 HSP90 一起在大分子复合物的组装过程中发挥作用，这些复合物通常参与细胞增殖。在这里，利用分离的 PIH 结构域进行的蛋白质组学实验揭示了 R2TP 的其他合作伙伴，包括结节性硬化症复合体（TSC）和许多转录复合体。TSC 是 mTORC1 的关键调节因子，由 TSC1、TSC2 和 TBC1D7 组成。我们展示了 TSC1 与 PIH1D1 的 PIH 磷酸化结合域的直接相互作用，令人惊讶的是，这种相互作用与磷酸化无关。通过使用突变体和 KO 细胞系，我们观察到 TSC2 与 HSP90 和 RPAP3 的 TPR 结构域有独立的相互作用。此外，PIH1D1 或 RUVBL1/2 ATPase 活性的失活抑制了 TSC1 与 TSC2 的结合。综上所述，这些数据提出了一个模型，在该模型中，R2TP 通过 PIH1D1 招募 TSC1，通过 RPAP3 和 HSP90 招募 TSC2，并利用 RUVBL1/2 的伴侣样活性来刺激它们的组装。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Molecular Biology 生物-生化与分子生物学

CiteScore

11.30

自引率

1.80%

发文量

412

审稿时长

28 days

期刊介绍： Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.