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Cohesin closes the door on coexpression 聚合素关闭了共表达之门
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-15 DOI: 10.1038/s41594-024-01404-5
George Andrew S. Inglis
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引用次数: 0
Putting together pieces of the LIN28A pathway puzzle 拼凑 LIN28A 通路拼图
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1038/s41594-024-01380-w
Alperen Yilmaz, Gulben Gurhan, Jacob H. Hanna
Two recent studies provide mechanistic insights into how LIN28A controls changes in cell fate identity, focusing on either a let-7-independent or let-7-dependent pathway of action involving LIN28A.
最近的两项研究从机理上揭示了 LIN28A 如何控制细胞命运特征的变化,重点研究了 LIN28A 依赖或不依赖 let-7 的作用途径。
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引用次数: 0
How protons shape AMPA receptor structure, function and diffusion at the synapse 质子如何塑造 AMPA 受体的结构、功能和在突触中的扩散
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1038/s41594-024-01371-x
The extracellular AMPA receptor N-terminal domain (NTD) affects synaptic strength by tuning receptor diffusion. We reveal that pH fluctuations accompanying synaptic activity alter NTD conformation of the functionally dominant GluA2 subunit, via proton sensing by an NTD histidine residue, thereby increasing gating kinetics and receptor diffusion at the synapse.
细胞外 AMPA 受体 N 端结构域(NTD)通过调整受体扩散影响突触强度。我们揭示了伴随突触活动的 pH 波动通过 NTD 组氨酸残基的质子感应改变了功能上占主导地位的 GluA2 亚基的 NTD 构象,从而增加了门控动力学和受体在突触处的扩散。
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引用次数: 0
Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization 质子触发的 AMPA 受体 N 端结构域重排影响受体动力学和突触定位
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1038/s41594-024-01369-5
Josip Ivica, Nejc Kejzar, Hinze Ho, Imogen Stockwell, Viktor Kuchtiak, Alexander M. Scrutton, Terunaga Nakagawa, Ingo H. Greger
AMPA glutamate receptors (AMPARs) are ion channel tetramers that mediate the majority of fast excitatory synaptic transmission. They are composed of four subunits (GluA1–GluA4); the GluA2 subunit dominates AMPAR function throughout the forebrain. Its extracellular N-terminal domain (NTD) determines receptor localization at the synapse, ensuring reliable synaptic transmission and plasticity. This synaptic anchoring function requires a compact NTD tier, stabilized by a GluA2-specific NTD interface. Here we show that low pH conditions, which accompany synaptic activity, rupture this interface. All-atom molecular dynamics simulations reveal that protonation of an interfacial histidine residue (H208) centrally contributes to NTD rearrangement. Moreover, in stark contrast to their canonical compact arrangement at neutral pH, GluA2 cryo-electron microscopy structures exhibit a wide spectrum of NTD conformations under acidic conditions. We show that the consequences of this pH-dependent conformational control are twofold: rupture of the NTD tier slows recovery from desensitized states and increases receptor mobility at mouse hippocampal synapses. Therefore, a proton-triggered NTD switch will shape both AMPAR location and kinetics, thereby impacting synaptic signal transmission. Combining patch-clamp electrophysiology, molecular dynamics simulations, cryo-electron microscopy and imaging of neuronal synapses, the authors reveal how AMPA glutamate receptors are regulated by protons that are released from synaptic vesicles during signal transmission.
AMPA 谷氨酸受体(AMPARs)是离子通道四聚体,介导了大部分快速兴奋性突触传递。它们由四个亚基(GluA1-GluA4)组成;GluA2 亚基主导整个前脑的 AMPAR 功能。其细胞外 N 端结构域(NTD)决定受体在突触处的定位,确保可靠的突触传递和可塑性。这种突触锚定功能需要一个紧凑的 NTD 层,由 GluA2 特异性 NTD 接口稳定。在这里,我们展示了伴随突触活动的低 pH 条件会导致这一界面破裂。全原子分子动力学模拟显示,界面组氨酸残基(H208)的质子化是导致 NTD 重排的主要原因。此外,与它们在中性 pH 值下的典型紧凑排列形成鲜明对比的是,GluA2 的冷冻电镜结构在酸性条件下呈现出广泛的 NTD 构象。我们的研究表明,这种依赖于 pH 值的构象控制具有双重后果:NTD 层的断裂会减缓从脱敏状态恢复的速度,并增加受体在小鼠海马突触中的流动性。因此,质子触发的 NTD 开关将影响 AMPAR 的位置和动力学,从而影响突触信号的传递。
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引用次数: 0
Sex chromosome-encoded protein homologs: current progress and open questions 性染色体编码蛋白同源物:当前进展与未决问题
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.1038/s41594-024-01362-y
Michael C. Owens, Amber Yanas, Kathy Fange Liu
The complexity of biological sex differences is markedly evident in human physiology and pathology. Although many of these differences can be ascribed to the expression of sex hormones, another contributor to sex differences lies in the sex chromosomes beyond their role in sex determination. Although largely nonhomologous, the human sex chromosomes express seventeen pairs of homologous genes, referred to as the ‘X–Y pairs.’ The X chromosome-encoded homologs of these Y-encoded proteins are crucial players in several cellular processes, and their dysregulation frequently results in disease development. Many diseases related to these X-encoded homologs present with sex-biased incidence or severity. By contrast, comparatively little is known about the differential functions of the Y-linked homologs. Here, we summarize and discuss the current understanding of five of these X–Y paired proteins, with recent evidence of differential functions and of having a potential link to sex biases in disease, highlighting how amino acid-level sequence differences may differentiate their functions and contribute to sex biases in human disease. Here, the authors examine and discuss the functional complexity and cellular implications of X–Y pairs, homologous genes expressed in the human sex chromosomes.
生物性别差异的复杂性在人类生理学和病理学中显而易见。虽然其中许多差异可归因于性激素的表达,但性别差异的另一个原因在于性染色体在性别决定中的作用。人类的性染色体虽然在很大程度上是非同源的,但它表达了 17 对同源基因,被称为 "X-Y 对"。这些 Y 编码蛋白的 X 染色体编码同源物在多个细胞过程中起着至关重要的作用,它们的失调经常导致疾病的发生。许多与这些 X 染色体编码同源物相关的疾病在发病率或严重程度上都存在性别差异。相比之下,人们对 Y 连锁同源物的不同功能知之甚少。在这里,我们总结并讨论了目前对其中五种 X-Y 配对蛋白的认识,这些蛋白最近有证据表明它们具有不同的功能,并与疾病中的性别偏见有潜在的联系,我们将重点介绍氨基酸水平的序列差异可能如何区分它们的功能并导致人类疾病中的性别偏见。
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引用次数: 0
Identifying nature’s smallest fractals 识别自然界最小的分形
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-30 DOI: 10.1038/s41594-024-01368-6
Kelli L. Hvorecny
Snowflakes, seashells and Romanesco broccoli are striking examples of fractal geometries in nature. A recent study published in Nature defines a set of molecular mechanisms for fractal assembly by identifying a nanometer-scale, regular fractal assembled from a native protein found in blue-green algae that likely arose as an evolutionary accident.
雪花、贝壳和西兰花都是自然界分形几何图形的鲜明代表。最近发表在《自然》(Nature)上的一项研究确定了一套分形组装的分子机制,该研究发现了一种纳米级的规则分形,由蓝绿藻中的一种本地蛋白质组装而成,这种分形很可能是进化过程中偶然出现的。
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引用次数: 0
Dissecting the mechanism of CRISPR–Cas technologies to design efficient biotechnologies 剖析 CRISPR-Cas 技术的机制,设计高效的生物技术
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1038/s41594-024-01366-8
Jasleen Gill
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引用次数: 0
Poised PABP–RNA hubs implement signal-dependent mRNA decay in development 定位的 PABP-RNA 中枢在发育过程中实现了信号依赖性 mRNA 衰减。
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-25 DOI: 10.1038/s41594-024-01363-x
Miha Modic, Klara Kuret, Sebastian Steinhauser, Rupert Faraway, Emiel van Genderen, Igor Ruiz de Los Mozos, Jona Novljan, Žiga Vičič, Flora C. Y. Lee, Derk ten Berge, Nicholas M. Luscombe, Jernej Ule
Signaling pathways drive cell fate transitions largely by changing gene expression. However, the mechanisms for rapid and selective transcriptome rewiring in response to signaling cues remain elusive. Here we use deep learning to deconvolve both the sequence determinants and the trans-acting regulators that trigger extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase kinase (MEK)-induced decay of the naive pluripotency mRNAs. Timing of decay is coupled to embryo implantation through ERK–MEK phosphorylation of LIN28A, which repositions pLIN28A to the highly A+U-rich 3′ untranslated region (3′UTR) termini of naive pluripotency mRNAs. Interestingly, these A+U-rich 3′UTR termini serve as poly(A)-binding protein (PABP)-binding hubs, poised for signal-induced convergence with LIN28A. The multivalency of AUU motifs determines the efficacy of pLIN28A–PABP convergence, which enhances PABP 3′UTR binding, decreases the protection of poly(A) tails and activates mRNA decay to enable progression toward primed pluripotency. Thus, the signal-induced convergence of LIN28A with PABP–RNA hubs drives the rapid selection of naive mRNAs for decay, enabling the transcriptome remodeling that ensures swift developmental progression. Here the authors show that, upon embryo implantation, signaling triggers a large-scale rearrangement of protein–RNA interactions. Phosphorylated LIN28A reassembles onto the 3′ untranslated region termini of pluripotency-associated mRNAs, where it converges with the binding of poly(A)-binding protein and drives selective mRNA decay.
信号通路主要通过改变基因表达来驱动细胞命运的转变。然而,对信号线索做出快速和选择性转录组重配的机制仍然难以捉摸。在这里,我们利用深度学习来解构引发细胞外信号调节激酶(ERK)-介导原活化蛋白激酶激酶(MEK)诱导的幼稚多能性mRNA衰变的序列决定因素和反式作用调节因子。通过ERK-MEK磷酸化LIN28A,使pLIN28A重新定位到幼稚多能性mRNA高度富含A+U的3'非翻译区(3'UTR)末端,衰变的时间与胚胎植入相关联。有趣的是,这些富含 A+U 的 3'UTR 末端是多聚(A)结合蛋白(PABP)的结合枢纽,可在信号诱导下与 LIN28A 聚合。AUU基序的多价性决定了pLIN28A-PABP汇聚的有效性,它能增强PABP 3'UTR的结合,减少对poly(A)尾的保护,激活mRNA的衰变,使其向原始多能性发展。因此,信号诱导的 LIN28A 与 PABP-RNA 中枢的聚合推动了对幼稚 mRNA 的快速衰变选择,实现了转录组的重塑,从而确保了快速的发育进程。
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引用次数: 0
Structural basis for activity switching in polymerases determining the fate of let-7 pre-miRNAs 决定 let-7 pre-miRNA 命运的聚合酶活性转换的结构基础。
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-25 DOI: 10.1038/s41594-024-01357-9
Gangshun Yi, Mingda Ye, Loic Carrique, Afaf El-Sagheer, Tom Brown, Chris J. Norbury, Peijun Zhang, Robert J. C. Gilbert
Tumor-suppressor let-7 pre-microRNAs (miRNAs) are regulated by terminal uridylyltransferases TUT7 and TUT4 that either promote let-7 maturation by adding a single uridine nucleotide to the pre-miRNA 3′ end or mark them for degradation by the addition of multiple uridines. Oligo-uridylation is increased in cells by enhanced TUT7/4 expression and especially by the RNA-binding pluripotency factor LIN28A. Using cryogenic electron microscopy, we captured high-resolution structures of active forms of TUT7 alone, of TUT7 plus pre-miRNA and of both TUT7 and TUT4 bound with pre-miRNA and LIN28A. Our structures reveal that pre-miRNAs engage the enzymes in fundamentally different ways depending on the presence of LIN28A, which clamps them onto the TUTs to enable processive 3′ oligo-uridylation. This study reveals the molecular basis for mono- versus oligo-uridylation by TUT7/4, as determined by the presence of LIN28A, and thus their mechanism of action in the regulation of cell fate and in cancer. Here, the authors show that cytoplasmic uridylyltransferases TUT7 and TUT4 bind let-7 pre-miRNA by alternative means in the absence and presence of Lin28A, which directly interacts with both RNA and enzyme to convert from a distributive to a processive mode of action.
抑制肿瘤的let-7前microRNA(miRNA)受末端尿苷酸转移酶TUT7和TUT4的调控,这两种酶要么通过在pre-miRNA 3'端添加单个尿苷核苷酸促进let-7的成熟,要么通过添加多个尿苷酸标记其降解。TUT7/4表达的增强,特别是RNA结合多能因子LIN28A的作用,使细胞中寡尿苷化增加。我们利用低温电子显微镜捕获了 TUT7 单独、TUT7 加上 pre-miRNA 以及 TUT7 和 TUT4 与 pre-miRNA 和 LIN28A 结合的高分辨率活性结构。我们的结构揭示出,pre-miRNA 与酶的结合方式根本不同,这取决于 LIN28A 的存在,LIN28A 将它们夹在 TUT 上,使 3' 寡核苷酸化成为可能。这项研究揭示了 LIN28A 的存在所决定的 TUT7/4 单尿嘧啶化与寡尿嘧啶化的分子基础,从而揭示了它们在细胞命运调控和癌症中的作用机制。
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引用次数: 0
The power of scientific collaborations and the future of structural biology 科学合作的力量与结构生物学的未来
IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1038/s41594-024-01358-8
Pedro Beltrao
The idea of a scientific discovery is often linked to the eureka moment of a lone scientist, which then transforms our thinking. However, scientific discoveries are never made by individuals in isolation. They build on the work of countless researchers, and often require interdisciplinary and collaborative teams of researchers.
科学发现的概念往往与科学家的 "尤里卡时刻 "联系在一起,它改变了我们的思维。然而,科学发现从来不是个人孤立完成的。它们建立在无数研究人员的工作基础之上,往往需要跨学科的研究人员团队合作完成。
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引用次数: 0
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Nature Structural & Molecular Biology
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