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An oligopeptide permease, OppABCD, requires an iron–sulfur cluster domain for functionality 寡肽渗透酶 OppABCD 需要铁硫簇结构域才能发挥功能。
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-28 DOI: 10.1038/s41594-024-01256-z
Xiaolin Yang, Tianyu Hu, Jingxi Liang, Zhiqi Xiong, Zhenli Lin, Yao Zhao, Xiaoting Zhou, Yan Gao, Shan Sun, Xiuna Yang, Luke W. Guddat, Haitao Yang, Zihe Rao, Bing Zhang
Oligopeptide permease, OppABCD, belongs to the type I ABC transporter family. Its role is to import oligopeptides into bacteria for nutrient uptake and to modulate the host immune response. OppABCD consists of a cluster C substrate-binding protein (SBP), OppA, membrane-spanning OppB and OppC subunits, and an ATPase, OppD, that contains two nucleotide-binding domains (NBDs). Here, using cryo-electron microscopy, we determined the high-resolution structures of Mycobacterium tuberculosis OppABCD in the resting state, oligopeptide-bound pre-translocation state, AMPPNP-bound pre-catalytic intermediate state and ATP-bound catalytic intermediate state. The structures show an assembly of a cluster C SBP with its ABC translocator and a functionally required [4Fe–4S] cluster-binding domain in OppD. Moreover, the ATP-bound OppABCD structure has an outward-occluded conformation, although no substrate was observed in the transmembrane cavity. Here, we reveal an oligopeptide recognition and translocation mechanism of OppABCD, which provides a perspective on how this and other type I ABC importers facilitate bulk substrate transfer across the lipid bilayer. Here, four cryo-EM structures of Mtb OppABCD reveal an assembly of a cluster C substrate-binding protein and its translocator, as well as the [4Fe–4S] cluster-regulated transport mechanism of oligopeptide permeases found in bacteria.
寡肽渗透酶 OppABCD 属于 I 型 ABC 转运体家族。它的作用是将寡肽导入细菌以摄取营养,并调节宿主的免疫反应。OppABCD由C簇底物结合蛋白(SBP)OppA、跨膜的OppB和OppC亚基以及含有两个核苷酸结合域(NBD)的ATP酶OppD组成。在这里,我们利用低温电子显微镜测定了结核分枝杆菌 OppABCD 在静止态、寡肽结合预转运态、AMPPNP 结合催化前中间态和 ATP 结合催化中间态的高分辨率结构。这些结构显示了簇 C SBP 与其 ABC 转运体以及 OppD 中功能所需的[4Fe-4S]簇结合域的组装。此外,与 ATP 结合的 OppABCD 结构具有外向包含构象,尽管在跨膜腔中没有观察到底物。在这里,我们揭示了 OppABCD 的寡肽识别和转运机制,从而为我们提供了一个视角,来了解该物种和其它 I 型 ABC 导入剂是如何促进大量底物跨脂质双分子层转移的。
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引用次数: 0
A personal perspective of the voltage-gated potassium channel studies 电压门控钾通道研究的个人视角。
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-28 DOI: 10.1038/s41594-024-01267-w
Lily Yeh Jan, Yuh Nung Jan
The identification of sodium and potassium currents as underlying action potential propagation, more than 70 years ago, opened a new avenue of research into the role of ion channels. In this Comment, we present our personal perspectives of the field, from the identification of Shaker as a potential potassium channel to the mechanistic insights available to us today.
70 多年前,钠和钾电流被确定为动作电位传播的基础,为研究离子通道的作用开辟了一条新途径。在这篇评论中,我们介绍了我们个人对这一领域的看法,从确定 Shaker 为潜在的钾通道,到我们今天所能获得的机理见解。
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引用次数: 0
Molecular stripping underpins derepression of a toxin–antitoxin system 分子剥离是解除毒素-抗毒素系统抑制的基础
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-27 DOI: 10.1038/s41594-024-01253-2
Grzegorz J. Grabe, Rachel T. Giorgio, Miłosz Wieczór, Bridget Gollan, Molly Sargen, Modesto Orozco, Stephen A. Hare, Sophie Helaine
Transcription factors control gene expression; among these, transcriptional repressors must liberate the promoter for derepression to occur. Toxin–antitoxin (TA) modules are bacterial elements that autoregulate their transcription by binding the promoter in a T:A ratio-dependent manner, known as conditional cooperativity. The molecular basis of how excess toxin triggers derepression has remained elusive, largely because monitoring the rearrangement of promoter–repressor complexes, which underpin derepression, is challenging. Here, we dissect the autoregulation of the Salmonella enterica tacAT3 module. Using a combination of assays targeting DNA binding and promoter activity, as well as structural characterization, we determine the essential TA and DNA elements required to control transcription, and we reconstitute a repression-to-derepression path. We demonstrate that excess toxin triggers molecular stripping of the repressor complex off the DNA through multiple allosteric changes causing DNA distortion and ultimately leading to derepression. Thus, our work provides important insight into the mechanisms underlying conditional cooperativity. Transcription of toxin–antitoxin modules is regulated by conditional cooperativity, where the toxin enables or disrupts antitoxin-driven repression. Here, the authors solve the structural basis for the conditional cooperativity of Salmonella TacAT3.
转录因子控制着基因的表达;其中,转录抑制因子必须释放启动子才能解除抑制。毒素-抗毒素(TA)模块是一种细菌元件,它通过以 T:A 比例依赖的方式与启动子结合来自动调节其转录,即所谓的条件合作性。过量毒素如何触发去抑制的分子基础一直难以捉摸,这主要是因为监测启动子-抑制因子复合物的重新排列具有挑战性,而启动子-抑制因子复合物是去抑制的基础。在这里,我们剖析了肠炎沙门氏菌 tacAT3 模块的自动调节。通过结合使用针对 DNA 结合和启动子活性的检测方法以及结构特征分析,我们确定了控制转录所需的基本 TA 和 DNA 元件,并重建了从抑制到去抑制的路径。我们证明,过量的毒素会通过多种异构变化引发DNA上的抑制复合物分子剥离,导致DNA变形,最终导致去抑制。因此,我们的工作为了解条件合作性的内在机制提供了重要启示。
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引用次数: 0
Structural insights into the decoding capability of isoleucine tRNAs with lysidine and agmatidine 异亮氨酸 tRNA 与赖氨酸和γ-脱氧核苷酸解码能力的结构性启示
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-27 DOI: 10.1038/s41594-024-01238-1
Naho Akiyama, Kensuke Ishiguro, Takeshi Yokoyama, Kenjyo Miyauchi, Asuteka Nagao, Mikako Shirouzu, Tsutomu Suzuki
The anticodon modifications of transfer RNAs (tRNAs) finetune the codon recognition on the ribosome for accurate translation. Bacteria and archaea utilize the modified cytidines, lysidine (L) and agmatidine (agm2C), respectively, in the anticodon of tRNAIle to decipher AUA codon. L and agm2C contain long side chains with polar termini, but their functions remain elusive. Here we report the cryogenic electron microscopy structures of tRNAsIle recognizing the AUA codon on the ribosome. Both modifications interact with the third adenine of the codon via a unique C–A geometry. The side chains extend toward 3′ direction of the mRNA, and the polar termini form hydrogen bonds with 2′-OH of the residue 3′-adjacent to the AUA codon. Biochemical analyses demonstrated that AUA decoding is facilitated by the additional interaction between the polar termini of the modified cytidines and 2′-OH of the fourth mRNA residue. We also visualized cyclic N6-threonylcarbamoyladenosine (ct6A), another tRNA modification, and revealed a molecular basis how ct6A contributes to efficient decoding. Precise protein synthesis is achieved by tRNA modifications. Here the authors revealed that modified cytidines in tRNAIle use their long side chains to make additional interactions with mRNA for stable tRNA binding on the ribosome.
转运核糖核酸(tRNA)的反密码子修饰可微调核糖体上的密码子识别,从而实现准确翻译。细菌和古细菌分别利用 tRNAIle 反密码子中的修饰胞嘧啶--赖氨酸(L)和琼脂糖嘧啶(agm2C)来破译 AUA 密码子。L 和 agm2C 含有极性末端的长侧链,但它们的功能仍然难以捉摸。在此,我们报告了在核糖体上识别 AUA 密码子的 tRNAsIle 的低温电子显微镜结构。这两种修饰都通过独特的 C-A 几何结构与密码子的第三个腺嘌呤相互作用。侧链向 mRNA 的 3′方向延伸,极性末端与 AUA 密码子相邻的 3′残基的 2′-OH形成氢键。生化分析表明,修饰胞嘧啶的极性末端与第四个 mRNA 残基的 2′-OH 之间的额外相互作用促进了 AUA 的解码。我们还对另一种 tRNA 修饰--环 N6-苏氨酰氨基甲酰基腺苷(ct6A)进行了可视化,并揭示了ct6A 如何促进高效解码的分子基础。
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引用次数: 0
Structures of the ribosome bound to EF-Tu–isoleucine tRNA elucidate the mechanism of AUG avoidance 与 EF-Tu-isoleucine tRNA 结合的核糖体结构阐明了 AUG 回避机制
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-27 DOI: 10.1038/s41594-024-01236-3
Mariia Yu. Rybak, Matthieu G. Gagnon
The frequency of errors upon decoding of messenger RNA by the bacterial ribosome is low, with one misreading event per 1 × 104 codons. In the universal genetic code, the AUN codon box specifies two amino acids, isoleucine and methionine. In bacteria and archaea, decoding specificity of the AUA and AUG codons relies on the wobble avoidance strategy that requires modification of C34 in the anticodon loop of isoleucine transfer RNAIleCAU (tRNAIleCAU). Bacterial tRNAIleCAU with 2-lysylcytidine (lysidine) at the wobble position deciphers AUA while avoiding AUG. Here we report cryo-electron microscopy structures of the Escherichia coli 70S ribosome complexed with elongation factor thermo unstable (EF-Tu) and isoleucine-tRNAIleLAU in the process of decoding AUA and AUG. Lysidine in tRNAIleLAU excludes AUG by promoting the formation of an unusual Hoogsteen purine–pyrimidine nucleobase geometry at the third position of the codon, weakening the interactions with the mRNA and destabilizing the EF-Tu ternary complex. Our findings elucidate the molecular mechanism by which tRNAIleLAU specifically decodes AUA over AUG. Rybak and Gagnon elucidate the mechanism of AUG codon avoidance by the minor isoleucine tRNA in Escherichia coli. The lysidinylated C34 in the anticodon loop of tRNAIle weakens interactions with the mRNA and destabilizes the EF-Tu ternary complex.
细菌核糖体解码信使 RNA 时出现错误的频率很低,每 1 × 104 个密码子才会出现一次误读。在通用遗传密码中,AUN 密码框指定两种氨基酸,即异亮氨酸和蛋氨酸。在细菌和古细菌中,AUA 和 AUG 密码子的解码特异性依赖于避免晃动的策略,该策略需要修改异亮氨酸转移核糖核酸 IleCAU(tRNAIleCAU)反密码子环中的 C34。细菌的 tRNAIleCAU 在摆动位置上添加了 2-赖氨酰胞苷(赖氨酸),可以在避免 AUG 的同时解读 AUA。在此,我们报告了大肠杆菌 70S 核糖体在解码 AUA 和 AUG 过程中与热不稳定延伸因子(EF-Tu)和异亮氨酸 tRNAIleLAU 复合物的冷冻电子显微镜结构。tRNAIleLAU 中的赖氨酸通过促进在密码子的第三个位置形成不寻常的霍格斯坦嘌呤-嘧啶核碱基几何形状来排除 AUG,从而削弱了与 mRNA 的相互作用并破坏了 EF-Tu 三元复合物的稳定性。我们的发现阐明了 tRNAIleLAU 特异性解码 AUA 而非 AUG 的分子机制。
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引用次数: 0
Structural basis of the histone ubiquitination read–write mechanism of RYBP–PRC1 RYBP-PRC1 组蛋白泛素化读写机制的结构基础。
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-25 DOI: 10.1038/s41594-024-01258-x
Maria Ciapponi, Elena Karlukova, Sven Schkölziger, Christian Benda, Jürg Müller
Histone H2A monoubiquitination (H2Aub1) by the PRC1 subunit RING1B entails a positive feedback loop, mediated by the RING1B-interacting protein RYBP. We uncover that human RYBP–PRC1 binds unmodified nucleosomes via RING1B but H2Aub1-modified nucleosomes via RYBP. RYBP interactions with both ubiquitin and the nucleosome acidic patch create the high binding affinity that favors RYBP- over RING1B-directed PRC1 binding to H2Aub1-modified nucleosomes; this enables RING1B to monoubiquitinate H2A in neighboring unmodified nucleosomes. Cryo-EM studies reveal that RYBP–PRC1 uses two distinct interfaces for binding unmodified and H2Aub1-modified nucleosomes. These binding modes enable the complex to generate H2Aub1 chromatin domains by a read–write mechanism.
组蛋白 H2A 被 PRC1 亚基 RING1B 单泛素化(H2Aub1)需要一个由 RING1B 相互作用蛋白 RYBP 介导的正反馈回路。我们发现人类 RYBP-PRC1 通过 RING1B 结合未修饰的核小体,但通过 RYBP 结合 H2Aub1 修饰的核小体。RYBP 与泛素和核小体酸性斑块的相互作用产生了高结合亲和力,这种亲和力有利于 RYBP 而不是 RING1B 引导 PRC1 与 H2Aub1 修饰的核小体结合;这使得 RING1B 能够单泛素化邻近未修饰核小体中的 H2A。
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引用次数: 0
Author Correction: Structure and interactions of the endogenous human Commander complex 作者更正:内源性人类 Commander 复合物的结构和相互作用。
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-19 DOI: 10.1038/s41594-024-01273-y
Saara Laulumaa, Esa-Pekka Kumpula, Juha T. Huiskonen, Markku Varjosalo
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引用次数: 0
Looking back at 30 years of Nature Structural & Molecular Biology 自然-结构与分子生物学》30 年回顾。
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-18 DOI: 10.1038/s41594-024-01248-z
Guy Riddihough, Christopher Surridge, Andreas G. Ladurner, Rosemary K. Clyne, Maria Hodges, Arianne Heinrichs, Katarzyna Marcinkiewicz, Florian Ullrich, Carolina Perdigoto, Sara Osman, Katarzyna Ciazynska, Dimitrios Typas
Over the past 30 years, Nature Structural & Molecular Biology (NSMB) has covered an enormous breadth of subjects in the broad field of molecular and structural biology. Here, some of the journal’s past and present editors recount their editorial experience at NSMB and some of the more memorable papers they worked on.
在过去的 30 年里,《自然-结构与分子生物学》(Nature Structural & Molecular Biology,NSMB)涵盖了分子和结构生物学这一广泛领域的众多主题。在这里,该杂志的一些前任和现任编辑将讲述他们在 NSMB 的编辑经历,以及他们参与编辑的一些令人难忘的论文。
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引用次数: 0
The impact of DNA methylation on CTCF-mediated 3D genome organization DNA 甲基化对 CTCF 介导的三维基因组组织的影响。
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-18 DOI: 10.1038/s41594-024-01241-6
Ana Monteagudo-Sánchez, Daan Noordermeer, Maxim V. C. Greenberg
Cytosine DNA methylation is a highly conserved epigenetic mark in eukaryotes. Although the role of DNA methylation at gene promoters and repetitive elements has been extensively studied, the function of DNA methylation in other genomic contexts remains less clear. In the nucleus of mammalian cells, the genome is spatially organized at different levels, and strongly influences myriad genomic processes. There are a number of factors that regulate the three-dimensional (3D) organization of the genome, with the CTCF insulator protein being among the most well-characterized. Pertinently, CTCF binding has been reported as being DNA methylation-sensitive in certain contexts, perhaps most notably in the process of genomic imprinting. Therefore, it stands to reason that DNA methylation may play a broader role in the regulation of chromatin architecture. Here we summarize the current understanding that is relevant to both the mammalian DNA methylation and chromatin architecture fields and attempt to assess the extent to which DNA methylation impacts the folding of the genome. The focus is in early embryonic development and cellular transitions when the epigenome is in flux, but we also describe insights from pathological contexts, such as cancer, in which the epigenome and 3D genome organization are misregulated. In this Review, the authors present an overview of our current understanding of the relationship between DNA methylation and three-dimensional chromatin architecture, discussing the extent to which DNA methylation may regulate the folding of the genome.
胞嘧啶 DNA 甲基化是真核生物中高度保守的表观遗传标记。虽然 DNA 甲基化在基因启动子和重复元件中的作用已被广泛研究,但 DNA 甲基化在其他基因组环境中的功能仍不太清楚。在哺乳动物细胞核中,基因组在不同水平上进行空间组织,并对无数基因组过程产生强烈影响。有许多因子可以调节基因组的三维(3D)组织,其中以 CTCF 绝缘蛋白的研究最为深入。更重要的是,据报道,在某些情况下,CTCF 的结合对 DNA 甲基化敏感,最明显的可能是在基因组印记过程中。因此,DNA 甲基化可能在染色质结构调控中发挥更广泛的作用。在此,我们总结了目前与哺乳动物 DNA 甲基化和染色质结构领域相关的认识,并尝试评估 DNA 甲基化对基因组折叠的影响程度。重点是表观基因组处于变化中的早期胚胎发育和细胞转换,但我们也描述了病理环境(如癌症)中表观基因组和三维基因组组织被误调的情况。
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引用次数: 0
Musings on art and science 关于艺术与科学的思考
IF 16.8 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-18 DOI: 10.1038/s41594-024-01266-x
In addition to the usual dose of compelling science, our March issue features thoughtful reflections on the last 30 years from readers, as well as past and present editors. Perhaps influenced by these pieces or by our stunning cover — or maybe it is just the changing seasons — we are in an introspective mood this month.
除了一如既往的引人入胜的科学内容外,我们的三月刊还刊登了读者以及前任和现任编辑对过去 30 年的深思。也许是受这些文章的影响,也许是受我们令人惊叹的封面的影响,也许只是因为季节的变化,本月我们沉浸在一种自省的情绪中。
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引用次数: 0
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