Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold.
Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold.
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DOI：
10.1038/s41467-022-34610-0
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发表时间：
2022-11-09
影响因子：
16.6
通讯作者：
Stanley, Robin E.
中科院分区：
文献类型：
--
作者：
Gordon, Jacob;Chapus, Fleur L.;Viverette, Elizabeth G.;Williams, Jason G.;Deterding, Leesa J.;Krahn, Juno M.;Borgnia, Mario J.;Rodriguez, Joseph;Warren, Alan J.;Stanley, Robin E.
PELP 1（Proline-，Glutamic acid-，Leucine-rich protein 1）是一种大的支架蛋白，在许多细胞途径中发挥作用，包括类固醇受体（SR）共激活、异染色质维持和核糖体生物发生。PELP 1是一种原癌基因，其表达在许多人类癌症中上调，但人们对PELP 1支架如何协调其多种细胞功能知之甚少。在这里，我们表明PELP 1作为人类Rix 1复合物的中心支架，其成员包括WDR 18，TEX 10和SENP 3。我们重建了哺乳动物Rix 1复合物，并确定了一个稳定的子复合物，包括保守的PELP 1 Rix 1结构域和WDR 18。我们确定了一个2.7 μ m的cryo-EM结构的子复合物揭示了一个相互连接的四聚体组装和PELP 1的信号基序的架构，包括11个LxxLL基序先前涉及SR信号和雌激素受体α（ERα）介导的转录的共激活。然而，结构显示这些基序中没有一个处于将支持SR结合的构象。总之，这项工作确立了PELP 1支架Rix 1复合物，与WDR 18的关联可能会指导PELP 1的活性远离SR共激活。PELP 1是一种大的支架蛋白，参与许多细胞活动，包括作为Rix 1复合物一部分的核糖体组装，包含PELP 1、WDR 18、TEX 10和其他组分。在这里，作者提出了PELP 1与其结合伴侣WDR 18复合的cryo-EM结构，揭示了PELP 1众多信号基序的结构。
PELP1 (Proline-, Glutamic acid-, Leucine-rich protein 1) is a large scaffolding protein that functions in many cellular pathways including steroid receptor (SR) coactivation, heterochromatin maintenance, and ribosome biogenesis. PELP1 is a proto-oncogene whose expression is upregulated in many human cancers, but how the PELP1 scaffold coordinates its diverse cellular functions is poorly understood. Here we show that PELP1 serves as the central scaffold for the human Rix1 complex whose members include WDR18, TEX10, and SENP3. We reconstitute the mammalian Rix1 complex and identified a stable sub-complex comprised of the conserved PELP1 Rix1 domain and WDR18. We determine a 2.7 Å cryo-EM structure of the subcomplex revealing an interconnected tetrameric assembly and the architecture of PELP1’s signaling motifs, including eleven LxxLL motifs previously implicated in SR signaling and coactivation of Estrogen Receptor alpha (ERα) mediated transcription. However, the structure shows that none of these motifs is in a conformation that would support SR binding. Together this work establishes that PELP1 scaffolds the Rix1 complex, and association with WDR18 may direct PELP1’s activity away from SR coactivation. PELP1 is a large scaffolding protein implicated in many cellular activities, including ribosome assembly as part of the Rix1 complex, comprising PELP1, WDR18, TEX10 and other components. Here, authors present the cryo-EM structure of PELP1 in complex with its binding partner WDR18, revealing the architecture of PELP1's numerous signaling motifs.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
3.3
作者：
Castle CD;Cassimere EK;Denicourt C
通讯作者：
Denicourt C
影响因子：
16.8
作者：
Barrio-Garcia, Clara;Thoms, Matthias;Hurt, Ed
通讯作者：
Hurt, Ed
影响因子：
3.3
作者：
Dang, Daniel N.;Raj, Ganesh;Peng, Yan
通讯作者：
Peng, Yan
影响因子：
14.9
作者：
Castle, Christopher D.;Sardana, Richa;Denicourt, Catherine
通讯作者：
Denicourt, Catherine