Nature Structural & Molecular Biology最新文献_第9页

Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice Shieldin 和 CST 共同协调 DNA 聚合酶依赖性尾端连接反应，与 53BP1 主导的修复途径选择无关

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-09-03 DOI: 10.1038/s41594-024-01381-9

Ashleigh King, Pia I. Reichl, Jean S. Metson, Robert Parker, Daniella Munro, Catarina Oliveira, Lucia Sommerova, Jordan R. Becker, Daniel Biggs, Chris Preece, Benjamin Davies, J. Ross Chapman

{"title":"Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice","authors":"Ashleigh King, Pia I. Reichl, Jean S. Metson, Robert Parker, Daniella Munro, Catarina Oliveira, Lucia Sommerova, Jordan R. Becker, Daniel Biggs, Chris Preece, Benjamin Davies, J. Ross Chapman","doi":"10.1038/s41594-024-01381-9","DOIUrl":"10.1038/s41594-024-01381-9","url":null,"abstract":"Tumor suppressor p53-binding protein 1 (53BP1) regulates DNA end joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting Rap1-interacting factor 1 homolog (RIF1) and shieldin, a poorly understood DNA-binding complex. The 53BP1–RIF1–shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate nonhomologous end joining (NHEJ). However, how this axis regulates DNA end joining and HR suppression remains unresolved. We investigated shieldin and its interplay with the Ctc1–Stn1–Ten1 (CST) complex, which was recently implicated downstream of 53BP1. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination coreliant on both complexes. Ataxia-telangiectasia mutated kinase-dependent DNA damage signaling underpins this cooperation, inducing physical interactions between these complexes that reveal shieldin as a DSB-responsive CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin–CST. Lastly, we demonstrate that 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient mice and cells independently of shieldin. These findings showcase the versatility of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins. Here, using mouse genetics, biochemistry and cell-based experiments, the authors reveal that shieldin primarily catalyzes DNA priming and polymerase-dependent fill-in synthesis at 5′ recessed DNA ends during the joining of activation-induced cytidine deaminase-dependent DNA breaks.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"86-97"},"PeriodicalIF":12.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01381-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural insight into synergistic activation of human 3-methylcrotonyl-CoA carboxylase 从结构上洞察人类 3-甲基巴豆酰-CoA羧化酶的协同激活作用

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-09-02 DOI: 10.1038/s41594-024-01379-3

Jiayue Su, Xuyang Tian, Hang Cheng, Desheng Liu, Ziyi Wang, Shan Sun, Hong-Wei Wang, Sen-Fang Sui

{"title":"Structural insight into synergistic activation of human 3-methylcrotonyl-CoA carboxylase","authors":"Jiayue Su, Xuyang Tian, Hang Cheng, Desheng Liu, Ziyi Wang, Shan Sun, Hong-Wei Wang, Sen-Fang Sui","doi":"10.1038/s41594-024-01379-3","DOIUrl":"10.1038/s41594-024-01379-3","url":null,"abstract":"The enzymes 3-methylcrotonyl-coenzyme A (CoA) carboxylase (MCC), pyruvate carboxylase and propionyl-CoA carboxylase belong to the biotin-dependent carboxylase family located in mitochondria. They participate in various metabolic pathways in human such as amino acid metabolism and tricarboxylic acid cycle. Many human diseases are caused by mutations in those enzymes but their structures have not been fully resolved so far. Here we report an optimized purification strategy to obtain high-resolution structures of intact human endogenous MCC, propionyl-CoA carboxylase and pyruvate carboxylase in different conformational states. We also determine the structures of MCC bound to different substrates. Analysis of MCC structures in different states reveals the mechanism of the substrate-induced, multi-element synergistic activation of MCC. These results provide important insights into the catalytic mechanism of the biotin-dependent carboxylase family and are of great value for the development of new drugs for the treatment of related diseases. This work reveals structures of biotin-dependent carboxylases in different states, provides notable insight into their catalytic mechanism and may help the development of new drugs for the treatment of related diseases.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"73-85"},"PeriodicalIF":12.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamics of an epigenetic regulator on chromatin observed at the single-molecule level 在单分子水平上观察染色质上表观遗传调节因子的动态变化

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-22 DOI: 10.1038/s41594-024-01374-8

引用次数: 0

Structural basis for lipid transfer by the ATG2A–ATG9A complex ATG2A-ATG9A 复合物脂质转移的结构基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-22 DOI: 10.1038/s41594-024-01376-6

Yang Wang, Selma Dahmane, Rujuan Ti, Xinyi Mai, Lizhe Zhu, Lars-Anders Carlson, Goran Stjepanovic

{"title":"Structural basis for lipid transfer by the ATG2A–ATG9A complex","authors":"Yang Wang, Selma Dahmane, Rujuan Ti, Xinyi Mai, Lizhe Zhu, Lars-Anders Carlson, Goran Stjepanovic","doi":"10.1038/s41594-024-01376-6","DOIUrl":"10.1038/s41594-024-01376-6","url":null,"abstract":"Autophagy is characterized by the formation of double-membrane vesicles called autophagosomes. Autophagy-related proteins (ATGs) 2A and 9A have an essential role in autophagy by mediating lipid transfer and re-equilibration between membranes for autophagosome formation. Here we report the cryo-electron microscopy structures of human ATG2A in complex with WD-repeat protein interacting with phosphoinositides 4 (WIPI4) at 3.2 Å and the ATG2A–WIPI4–ATG9A complex at 7 Å global resolution. On the basis of molecular dynamics simulations, we propose a mechanism of lipid extraction from the donor membranes. Our analysis revealed 3:1 stoichiometry of the ATG9A–ATG2A complex, directly aligning the ATG9A lateral pore with ATG2A lipid transfer cavity, and an interaction of the ATG9A trimer with both the N-terminal and the C-terminal tip of rod-shaped ATG2A. Cryo-electron tomography of ATG2A liposome-binding states showed that ATG2A tethers lipid vesicles at different orientations. In summary, this study provides a molecular basis for the growth of the phagophore membrane and lends structural insights into spatially coupled lipid transport and re-equilibration during autophagosome formation. The study presents cryo-electron microscopy structures of human autophagy-related protein (ATG) 2A in complex with WD-repeat protein interacting with phosphoinositides 4 (WIPI4) and the ATG2A–WIPI4–ATG9A complex, providing insights into spatially coupled lipid transport and re-equilibration during autophagosome formation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"35-47"},"PeriodicalIF":12.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Nature Structural & Molecular Biology Pub Date : 2024-08-21 DOI: 10.1038/s41594-024-01380-w

Alperen Yilmaz, Gulben Gurhan, Jacob H. Hanna

引用次数: 0

Differential dynamics specify MeCP2 function at nucleosomes and methylated DNA 核小体和甲基化 DNA 上 MeCP2 功能的差异动力学说明

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-20 DOI: 10.1038/s41594-024-01373-9

Gabriella N. L. Chua, John W. Watters, Paul Dominic B. Olinares, Masuda Begum, Lauren E. Vostal, Joshua A. Luo, Brian T. Chait, Shixin Liu

{"title":"Differential dynamics specify MeCP2 function at nucleosomes and methylated DNA","authors":"Gabriella N. L. Chua, John W. Watters, Paul Dominic B. Olinares, Masuda Begum, Lauren E. Vostal, Joshua A. Luo, Brian T. Chait, Shixin Liu","doi":"10.1038/s41594-024-01373-9","DOIUrl":"10.1038/s41594-024-01373-9","url":null,"abstract":"Methyl-CpG-binding protein 2 (MeCP2) is an essential chromatin-binding protein whose mutations cause Rett syndrome (RTT), a severe neurological disorder that primarily affects young females. The canonical view of MeCP2 as a DNA methylation-dependent transcriptional repressor has proven insufficient to describe its dynamic interaction with chromatin and multifaceted roles in genome organization and gene expression. Here we used single-molecule correlative force and fluorescence microscopy to directly visualize the dynamics of wild-type and RTT-causing mutant MeCP2 on DNA. We discovered that MeCP2 exhibits distinct one-dimensional diffusion kinetics when bound to unmethylated versus CpG methylated DNA, enabling methylation-specific activities such as co-repressor recruitment. We further found that, on chromatinized DNA, MeCP2 preferentially localizes to nucleosomes and stabilizes them from mechanical perturbation. Our results reveal the multimodal behavior of MeCP2 on chromatin that underlies its DNA methylation- and nucleosome-dependent functions and provide a biophysical framework for dissecting the molecular pathology of RTT mutations. Using single-molecule techniques, the authors find that the methyl-CpG-binding protein MeCP2, whose mutations cause Rett syndrome, exhibits distinctive behaviors when bound to nucleosomes versus free DNA, thus directing its multifaceted functions on chromatin.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1789-1797"},"PeriodicalIF":12.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01373-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural plasticity of bacterial ESCRT-III protein PspA in higher-order assemblies 细菌 ESCRT-III 蛋白 PspA 在高阶组装中的结构可塑性

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-16 DOI: 10.1038/s41594-024-01359-7

Benedikt Junglas, Esther Hudina, Philipp Schönnenbeck, Ilona Ritter, Anja Heddier, Beatrix Santiago-Schübel, Pitter F. Huesgen, Dirk Schneider, Carsten Sachse

{"title":"Structural plasticity of bacterial ESCRT-III protein PspA in higher-order assemblies","authors":"Benedikt Junglas, Esther Hudina, Philipp Schönnenbeck, Ilona Ritter, Anja Heddier, Beatrix Santiago-Schübel, Pitter F. Huesgen, Dirk Schneider, Carsten Sachse","doi":"10.1038/s41594-024-01359-7","DOIUrl":"10.1038/s41594-024-01359-7","url":null,"abstract":"Eukaryotic members of the endosome sorting complex required for transport-III (ESCRT-III) family have been shown to form diverse higher-order assemblies. The bacterial phage shock protein A (PspA) has been identified as a member of the ESCRT-III superfamily, and PspA homo-oligomerizes to form rod-shaped assemblies. As observed for eukaryotic ESCRT-III, PspA forms tubular assemblies of varying diameters. Using electron cryo-electron microscopy, we determined 61 Synechocystis PspA structures and observed in molecular detail how the structural plasticity of PspA rods is mediated by conformational changes at three hinge regions in the monomer and by the fixed and changing molecular contacts between protomers. Moreover, we reduced and increased the structural plasticity of PspA rods by removing the loop connecting helices α3/α4 and the addition of nucleotides, respectively. Based on our analysis of PspA-mediated membrane remodeling, we suggest that the observed mode of structural plasticity is a prerequisite for the biological function of ESCRT-III members. Using cryo-EM, the authors revealed structures of ESCRT-III superfamily member PspA and the molecular basis of structural plasticity that enables assembly modulations by the addition of nucleotides and targeted mutations.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"23-34"},"PeriodicalIF":12.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01359-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A PRE loop at the dac locus acts as a topological chromatin structure that restricts and specifies enhancer–promoter communication dac 基因座上的 PRE 环是一种拓扑染色质结构，它限制并指定了增强子与启动子之间的交流

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-16 DOI: 10.1038/s41594-024-01375-7

Sandrine Denaud, Marion Bardou, Giorgio-Lucio Papadopoulos, Stefan Grob, Marco Di Stefano, Gonzalo Sabarís, Marcelo Nollmann, Bernd Schuettengruber, Giacomo Cavalli

{"title":"A PRE loop at the dac locus acts as a topological chromatin structure that restricts and specifies enhancer–promoter communication","authors":"Sandrine Denaud, Marion Bardou, Giorgio-Lucio Papadopoulos, Stefan Grob, Marco Di Stefano, Gonzalo Sabarís, Marcelo Nollmann, Bernd Schuettengruber, Giacomo Cavalli","doi":"10.1038/s41594-024-01375-7","DOIUrl":"10.1038/s41594-024-01375-7","url":null,"abstract":"Three-dimensional (3D) genome folding has a fundamental role in the regulation of developmental genes by facilitating or constraining chromatin interactions between cis-regulatory elements (CREs). Polycomb response elements (PREs) are a specific kind of CRE involved in the memory of transcriptional states in Drosophila melanogaster. PREs act as nucleation sites for Polycomb group (PcG) proteins, which deposit the repressive histone mark H3K27me3, leading to the formation of a class of topologically associating domain (TAD) called a Polycomb domain. PREs can establish looping contacts that stabilize the gene repression of key developmental genes during development. However, the mechanism by which PRE loops fine-tune gene expression is unknown. Using clustered regularly interspaced short palindromic repeats and Cas9 genome engineering, we specifically perturbed PRE contacts or enhancer function and used complementary approaches including 4C-seq, Hi-C and Hi-M to analyze how chromatin architecture perturbation affects gene expression. Our results suggest that the PRE loop at the dac gene locus acts as a constitutive 3D chromatin scaffold during Drosophila development that forms independently of gene expression states and has a versatile function; it restricts enhancer–promoter communication and contributes to enhancer specificity. Combining genome engineering, epigenomics and multiplex three-dimensional microscopy approaches, the authors show that PRE chromatin loops form a topological scaffold, restricting promoter–enhancer communication and contributing to enhancer–promoter specificity.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1942-1954"},"PeriodicalIF":12.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01375-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Topoisomerase-modulated genome-wide DNA supercoiling domains colocalize with nuclear compartments and regulate human gene expression 拓扑异构酶调控的全基因组DNA超卷曲结构域与核分区共定位并调控人类基因表达

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-16 DOI: 10.1038/s41594-024-01377-5

Qian Yao, Linying Zhu, Zhen Shi, Subhadra Banerjee, Chongyi Chen

{"title":"Topoisomerase-modulated genome-wide DNA supercoiling domains colocalize with nuclear compartments and regulate human gene expression","authors":"Qian Yao, Linying Zhu, Zhen Shi, Subhadra Banerjee, Chongyi Chen","doi":"10.1038/s41594-024-01377-5","DOIUrl":"10.1038/s41594-024-01377-5","url":null,"abstract":"DNA supercoiling is a biophysical feature of the double helix with a pivotal role in biological processes. However, understanding of DNA supercoiling in the chromatin remains limited. Here, we developed azide-trimethylpsoralen sequencing (ATMP-seq), a DNA supercoiling assay offering quantitative accuracy while minimizing genomic bias and background noise. Using ATMP-seq, we directly visualized transcription-dependent negative and positive twin-supercoiled domains around genes and mapped kilobase-resolution DNA supercoiling throughout the human genome. Remarkably, we discovered megabase-scale supercoiling domains (SDs) across all chromosomes that are modulated mainly by topoisomerases I and IIβ. Transcription activities, but not the consequent supercoiling accumulation in the local region, contribute to SD formation, indicating the long-range propagation of transcription-generated supercoiling. Genome-wide SDs colocalize with A/B compartments in both human and Drosophila cells but are distinct from topologically associating domains (TADs), with negative supercoiling accumulation at TAD boundaries. Furthermore, genome-wide DNA supercoiling varies between cell states and types and regulates human gene expression, underscoring the importance of supercoiling dynamics in chromatin regulation and function. Here, the authors develop an assay to measure DNA supercoiling, revealing DNA supercoiling domains across the human genome that are modulated by topoisomerase and showing their colocalization with nuclear compartments and impact on gene expression.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"48-61"},"PeriodicalIF":12.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Nature Structural & Molecular Biology Pub Date : 2024-08-13 DOI: 10.1038/s41594-024-01371-x

引用次数: 0