Nature Structural & Molecular Biology最新文献_第3页

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

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

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

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

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

Nature Structural & 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

{"title":"Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization","authors":"Josip Ivica, Nejc Kejzar, Hinze Ho, Imogen Stockwell, Viktor Kuchtiak, Alexander M. Scrutton, Terunaga Nakagawa, Ingo H. Greger","doi":"10.1038/s41594-024-01369-5","DOIUrl":"10.1038/s41594-024-01369-5","url":null,"abstract":"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.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1601-1613"},"PeriodicalIF":12.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01369-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973779","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 basis of LRPPRC–SLIRP-dependent translation by the mitoribosome 米托里伯体依赖 LRPPRC-SLIRP 翻译的结构基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-12 DOI: 10.1038/s41594-024-01365-9

Vivek Singh, J. Conor Moran, Yuzuru Itoh, Iliana C. Soto, Flavia Fontanesi, Mary Couvillion, Martijn A. Huynen, L. Stirling Churchman, Antoni Barrientos, Alexey Amunts

{"title":"Structural basis of LRPPRC–SLIRP-dependent translation by the mitoribosome","authors":"Vivek Singh, J. Conor Moran, Yuzuru Itoh, Iliana C. Soto, Flavia Fontanesi, Mary Couvillion, Martijn A. Huynen, L. Stirling Churchman, Antoni Barrientos, Alexey Amunts","doi":"10.1038/s41594-024-01365-9","DOIUrl":"10.1038/s41594-024-01365-9","url":null,"abstract":"In mammalian mitochondria, mRNAs are cotranscriptionally stabilized by the protein factor LRPPRC (leucine-rich pentatricopeptide repeat-containing protein). Here, we characterize LRPPRC as an mRNA delivery factor and report its cryo-electron microscopy structure in complex with SLIRP (SRA stem-loop-interacting RNA-binding protein), mRNA and the mitoribosome. The structure shows that LRPPRC associates with the mitoribosomal proteins mS39 and the N terminus of mS31 through recognition of the LRPPRC helical repeats. Together, the proteins form a corridor for handoff of the mRNA. The mRNA is directly bound to SLIRP, which also has a stabilizing function for LRPPRC. To delineate the effect of LRPPRC on individual mitochondrial transcripts, we used RNA sequencing, metabolic labeling and mitoribosome profiling, which showed a transcript-specific influence on mRNA translation efficiency, with cytochrome c oxidase subunit 1 and 2 translation being the most affected. Our data suggest that LRPPRC–SLIRP acts in recruitment of mitochondrial mRNAs to modulate their translation. Collectively, the data define LRPPRC–SLIRP as a regulator of the mitochondrial gene expression system. Here, using cryo-electron microscopy to study the structure of LRPPRC (leucine-rich pentatricopeptide repeat-containing protein) in complex with SLIRP (SRA stem-loop-interacting RNA-binding protein), mRNA and the mitoribosome, the authors show that LRPPRC facilitates mRNA handoff to the mitoribosome and regulates the expression of several mitochondrial genes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1838-1847"},"PeriodicalIF":12.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01365-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918825","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

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

Nature Structural & Molecular Biology Pub Date : 2024-08-09 DOI: 10.1038/s41594-024-01362-y

Michael C. Owens, Amber Yanas, Kathy Fange Liu

{"title":"Sex chromosome-encoded protein homologs: current progress and open questions","authors":"Michael C. Owens, Amber Yanas, Kathy Fange Liu","doi":"10.1038/s41594-024-01362-y","DOIUrl":"10.1038/s41594-024-01362-y","url":null,"abstract":"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.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 8","pages":"1156-1166"},"PeriodicalIF":12.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908894","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

Structural basis of RfaH-mediated transcription–translation coupling RfaH 介导的转录-翻译耦合的结构基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-08 DOI: 10.1038/s41594-024-01372-w

Vadim Molodtsov, Chengyuan Wang, Jing Zhang, Jason T. Kaelber, Gregor Blaha, Richard H. Ebright

{"title":"Structural basis of RfaH-mediated transcription–translation coupling","authors":"Vadim Molodtsov, Chengyuan Wang, Jing Zhang, Jason T. Kaelber, Gregor Blaha, Richard H. Ebright","doi":"10.1038/s41594-024-01372-w","DOIUrl":"10.1038/s41594-024-01372-w","url":null,"abstract":"The NusG paralog RfaH mediates bacterial transcription–translation coupling in genes that contain a DNA sequence element, termed an ops site, required for pausing RNA polymerase (RNAP) and for loading RfaH onto the paused RNAP. Here, we report cryo-electron microscopy structures of transcription–translation complexes (TTCs) containing Escherichia coli RfaH. The results show that RfaH bridges RNAP and the ribosome, with the RfaH N-terminal domain interacting with RNAP and the RfaH C-terminal domain interacting with the ribosome. The results show that the distribution of translational and orientational positions of RNAP relative to the ribosome in RfaH-coupled TTCs is more restricted than in NusG-coupled TTCs because of the more restricted flexibility of the RfaH interdomain linker. The results further suggest that the structural organization of RfaH-coupled TTCs in the ‘loading state’, in which RNAP and RfaH are located at the ops site during formation of the TTC, is the same as the structural organization of RfaH-coupled TTCs in the ‘loaded state’, in which RNAP and RfaH are located at positions downstream of the ops site during function of the TTC. The results define the structural organization of RfaH-containing TTCs and set the stage for analysis of functions of RfaH during translation initiation and transcription–translation coupling. Here, the authors report cryo-electron microscopy structures of Escherichia coli transcription–translation complexes containing the transcription–translation coupling factor RfaH, showing that RfaH physically bridges RNA polymerase and the ribosome.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1932-1941"},"PeriodicalIF":12.5,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904613","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

Structural basis for processive daughter-strand synthesis and proofreading by the human leading-strand DNA polymerase Pol ε 人类前导链 DNA 聚合酶 Pol ε 进行子链合成和校对的结构基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-08-07 DOI: 10.1038/s41594-024-01370-y

Johann J. Roske, Joseph T. P. Yeeles

{"title":"Structural basis for processive daughter-strand synthesis and proofreading by the human leading-strand DNA polymerase Pol ε","authors":"Johann J. Roske, Joseph T. P. Yeeles","doi":"10.1038/s41594-024-01370-y","DOIUrl":"10.1038/s41594-024-01370-y","url":null,"abstract":"During chromosome replication, the nascent leading strand is synthesized by DNA polymerase epsilon (Pol ε), which associates with the sliding clamp processivity factor proliferating cell nuclear antigen (PCNA) to form a processive holoenzyme. For high-fidelity DNA synthesis, Pol ε relies on nucleotide selectivity and its proofreading ability to detect and excise a misincorporated nucleotide. Here, we present cryo-electron microscopy (cryo-EM) structures of human Pol ε in complex with PCNA, DNA and an incoming nucleotide, revealing how Pol ε associates with PCNA through its PCNA-interacting peptide box and additional unique features of its catalytic domain. Furthermore, by solving a series of cryo-EM structures of Pol ε at a mismatch-containing DNA, we elucidate how Pol ε senses and edits a misincorporated nucleotide. Our structures delineate steps along an intramolecular switching mechanism between polymerase and exonuclease activities, providing the basis for a proofreading mechanism in B-family replicative polymerases. Using cryo-electron microscopy, the authors deepen our mechanistic understanding of nascent leading-strand synthesis during human DNA replication and provide the basis for a proofreading mechanism in B-family replicative polymerases.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1921-1931"},"PeriodicalIF":12.5,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01370-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899782","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