寡聚和独特的tRNA结合环是人类精氨酸转移酶功能的重要调节因子-动脉网

Oligomerization and a distinct tRNA-binding loop are important regulators of human arginyl-transferase function

Nature 等信源发布 2024-07-28 10:07

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AbstractThe arginyl-transferase ATE1 is a tRNA-dependent enzyme that covalently attaches an arginine molecule to a protein substrate. Conserved from yeast to humans, ATE1 deficiency in mice correlates with defects in cardiovascular development and angiogenesis and results in embryonic lethality, while conditional knockouts exhibit reproductive, developmental, and neurological deficiencies.

摘要精氨酸转移酶ATE1是一种tRNA依赖性酶，可将精氨酸分子共价连接到蛋白质底物上。从酵母到人类都是保守的，小鼠ATE1缺陷与心血管发育和血管生成缺陷相关，并导致胚胎致死率，而条件性敲除则表现出生殖，发育和神经缺陷。

Despite the recent revelation of the tRNA binding mechanism and the catalytic cycle of yeast ATE1, the structure-function relationship of ATE1 in higher organisms is not well understood. In this study, we present the three-dimensional structure of human ATE1 in an apo-state and in complex with its tRNA cofactor and a peptide substrate.

尽管最近揭示了酵母ATE1的tRNA结合机制和催化循环，但ATE1在高等生物中的结构-功能关系尚不清楚。在这项研究中，我们介绍了载脂蛋白状态的人ATE1的三维结构，并与其tRNA辅因子和肽底物复合。

In contrast to its yeast counterpart, human ATE1 forms a symmetric homodimer, which dissociates upon binding of a substrate. Furthermore, human ATE1 includes a unique and extended loop that wraps around tRNAArg, creating extensive contacts with the T-arm of the tRNA cofactor. Substituting key residues identified in the substrate binding site of ATE1 abolishes enzymatic activity and results in the accumulation of ATE1 substrates in cells..

与其酵母对应物相反，人ATE1形成对称的同型二聚体，其在底物结合后解离。此外，人类ATE1包括一个独特且扩展的环，该环包裹在tRNAArg周围，与tRNA辅因子的T臂产生广泛的接触。替代ATE1底物结合位点中鉴定的关键残基会消除酶活性，并导致ATE1底物在细胞中积累。。

IntroductionConserved from yeast to plants and mammals, arginyl-tRNA-protein transferase 1 (ATE1) is an enzyme that covalently transfers an arginine (arginylation) from tRNAArg to its protein substrates and has been implicated in a multitude of biological processes, including, prominently, in protein degradation1,2,3,4.

简介从酵母到植物和哺乳动物保守，精氨酰-tRNA蛋白转移酶1（ATE1）是一种酶，可将精氨酸（精氨酰化）从tRNAArg共价转移到其蛋白质底物，并涉及多种生物过程，包括显着的蛋白质降解1,2,3,4。

Unlike other degron systems, the Arg/N-degron branch is unique as its action requires ATE1-mediated protein arginylation in a tRNA-dependent manner. Specifically, ATE1 transfers the nutrient arginine from high-energy arginyl-tRNAArg to substrate proteins containing an exposed N-terminal aspartate/glutamate residue (Fig. 1a).

与其他degron系统不同，Arg/N-degron分支是独特的，因为其作用需要ATE1介导的蛋白质精氨酸化以tRNA依赖性方式。具体而言，ATE1将营养精氨酸从高能精氨酰-tRNAArg转移到含有暴露的N端天冬氨酸/谷氨酸残基的底物蛋白上（图1a）。

Arginyl-tRNA synthetase (ArgRS) then recharges tRNAArg released from the reaction. Therefore, this mechanism inherently links fundamental cellular processes, including protein synthesis, nutrient availability and metabolism, and protein turnover.Fig. 1: Recombinant human ATE1 is active and forms a dimer.a Overview of protein arginylation and protein synthesis.

然后，精氨酰-tRNA合成酶（ArgRS）重新充电从反应中释放的tRNAArg。因此，这种机制内在地联系了基本的细胞过程，包括蛋白质合成，营养物质的可用性和代谢以及蛋白质周转。图1：重组人ATE1具有活性并形成二聚体。蛋白质精氨酸化和蛋白质合成概述。

b In vitro arginylation of the indicated substrate peptide using recombinantly purified ATE1 monitored by liquid chromatography–mass spectrometry (LC-MS) analysis. c Intact protein analysis of recombinantly purified human ATE1 after cleaving GST-tag by LC-MS. d Overview of the in-bacteria arginylation assay.

b使用通过液相色谱-质谱（LC-MS）分析监测的重组纯化的ATE1对指定底物肽进行体外精氨酰化。c通过LC-MS切割GST标签后重组纯化的人ATE1的完整蛋白质分析。d细菌内精氨酸化测定的概述。

The protein of interest (POI) fused to an N-terminal SUMO tag is co-expressed with Ulp1 protease and ATE1, producing recombinantly expressed arginylated proteins. e In E. coli arginylation of indicated substrate peptide co-expressed with ATE1 was monitored by intact protein analysis. f Superimposed 1H,15N heteronuclear single quantum coherence (HSQC) spectra of the substrate DDIAA-Ub co-expressed with ATE1 (black) with recombinantly purified corresponding Nt-arginylated pro.

与N端SUMO标签融合的目标蛋白（POI）与Ulp1蛋白酶和ATE1共表达，产生重组表达的精氨酸化蛋白。通过完整蛋白质分析监测与ATE1共表达的指定底物肽在大肠杆菌中的精氨酸化。f与ATE1（黑色）共表达的底物DDIAA-Ub的1H，15N异核单量子相干（HSQC）光谱与重组纯化的相应的Nt-精氨酰化pro叠加。

Data availability

数据可用性

The cryo-EM maps have been deposited in the Electron Microscopy Data Bank under accession codes EMD-41770 and EMD-42071. The atomic coordinates for the deposited map have been deposited in the Protein Data Bank under accession codes 8TZV and 8UAU. Source data are provided with this paper. All other relevant data supporting the key findings of this study are available within the article, its Supplementary Information or from the corresponding authors upon request.

低温电磁图已保存在电子显微镜数据库中，登录号为EMD-41770和EMD-42071。已保存地图的原子坐标已保存在蛋白质数据库中，登录号为8TZV和8UAU。本文提供了源数据。支持本研究主要发现的所有其他相关数据均可在文章及其补充信息中获得，或应要求从通讯作者处获得。

The structural data used in this study are available in the PDB database under accession codes 7UXA, 8E3S and 8FZR. Source data are provided with this paper..

本研究中使用的结构数据可在PDB数据库中以登录号7UXA，8E3S和8FZR获得。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank Drs. Mehaffey and Ebmeier at the University of Colorado Boulder Mass Spectrometry Facility for help with collecting and analyzing samples. This work was supported by grants from NIH R00 CA241301 and R35 GM150678 to Y.Z., R01 GM133841, RM1 GM142002, and R01 CA240993 to D.J.T and Case Comprehensive Cancer Center (P30CA043703 to Y.Z.

下载参考文献致谢我们感谢科罗拉多大学博尔德分校质谱设施的Mehaffey博士和Ebmeier博士在收集和分析样品方面的帮助。这项工作得到了NIH R00 CA241301和R35 GM150678给Y.Z.，R01 GM133841，RM1 GM142002和R01 CA240993给D.J.T和病例综合癌症中心（P30CA043703给Y.Z。

and D.J.T.) and the Basic Science Research Programs of the NRF funded by the Ministry of Science, ICT, and Future Planning (MSIP) (NRF-2020R1A5A1019023 and NRF-2021R1A2B5B03002614 to Y.T.K., and RS-2023-00249464 to C.H.J.). We are grateful to the Cryo-Electron Microscopy Core at the CWRU School of Medicine and K.

和D.J.T.）以及由科学，ICT和未来规划部（MSIP）资助的NRF基础科学研究计划（NRF-2020R1A5A1019023和NRF-2021R1A2B5B0302614至Y.T.K.，RS-2023-00249464至C.H.J.）。我们感谢CWRU医学院和K的低温电子显微镜核心。

Li and K. Whiddon for access to the sample preparation and cryo-EM instrumentation. Computational support was provided by the Case Western Reserve University High-Performance Computing Cluster. This publication was made possible by the Clinical and Translational Science Collaborative of Cleveland, UL1TR0002548 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research.

Li和K.Whiddon获得样品制备和低温电磁仪器。凯斯西储大学高性能计算集群提供了计算支持。本出版物由克利夫兰临床与转化科学合作组织UL1TR0002548提供，该合作组织来自美国国立卫生研究院国家转化科学促进中心（NCATS）和美国国立卫生研究院医学研究路线图。

This study made use of NMRbox: National Center for Biomolecular NMR Data Processing and Analysis, a Biomedical Technology Research Resource (BTRR), which is supported by NIH grant P41GM111135 (NIGMS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.Author informationAuthor notesThese authors contributed equally: Xin Lan, Wei Huang, Su Bin Kim.These authors jointly supervised this work: Chang Hoon Ji, Derek J.

这项研究利用了NMRbox：国家生物分子NMR数据处理和分析中心，这是一种生物医学技术研究资源（BTRR），由NIH资助P41GM111135（NIGMS）支持。其内容仅由作者负责，不一定代表NIH的官方观点。作者信息作者注意到这些作者做出了同样的贡献：Xin Lan，Wei Huang，Su Bin Kim。这些作者共同监督了这项工作：Chang Hoon Ji，Derek J。

Taylor, Yi ZhangAuthors and AffiliationsDepartment of Biochemistry, Case Western Reserve University, Cleveland, OH, USAXin Lan, Dechen Fu, .

Taylor，Yi Zhang作者和附属机构凯斯西储大学生物化学系，俄亥俄州克利夫兰，USAXin Lan，Dechen Fu。

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PubMed Google ScholarContributionsX.L., W.H., S.B.K., D.F., T.A., J.L., and U.B. performed experiments and together with C.H.J., Y.T.K., D.J.T., and Y.Z. analyzed the data. C.H.J., D.J.T., and Y.Z. wrote the manuscript with input from all authors.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献x。五十、，W.H.，S.B.K.，D.F.，T.A.，J.L。和U.B.进行了实验，并与C.H.J.，Y.T.K.，D.J.T。和Y.Z.一起分析了数据。C、 H.J.，D.J.T。和Y.Z.在所有作者的意见下撰写了手稿。通讯作者通讯。

Chang Hoon Ji, Derek J. Taylor or Yi Zhang.Ethics declarations

Chang Hoon Ji，Derek J.Taylor或Yi Zhang。道德宣言

Competing interests

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W.H. and D.J.T. provide consultation for, and D.J.T. has ownership interests in, Rappta Therapeutics, which focuses on areas of research unrelated to the present study. The remaining authors declare no competing interests.

W、 H.和D.J.T.为Rappta Therapeutics提供咨询，D.J.T.拥有所有权，Rappta Therapeutics专注于与本研究无关的研究领域。其余作者声明没有利益冲突。

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Nature Communications thanks Andrei Korostelev, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleLan, X., Huang, W., Kim, S.B. et al. Oligomerization and a distinct tRNA-binding loop are important regulators of human arginyl-transferase function.

转载和许可本文引用本文Lan，X.，Huang，W.，Kim，S.B.等人。寡聚化和独特的tRNA结合环是人类精氨酸转移酶功能的重要调节剂。

Nat Commun 15, 6350 (2024). https://doi.org/10.1038/s41467-024-50719-wDownload citationReceived: 29 October 2023Accepted: 18 July 2024Published: 28 July 2024DOI: https://doi.org/10.1038/s41467-024-50719-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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