Nature Structural & Molecular Biology最新文献_第10页

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

Identifying nature’s smallest fractals 识别自然界最小的分形

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-07-30 DOI: 10.1038/s41594-024-01368-6

Kelli L. Hvorecny

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

Nature Structural & Molecular Biology Pub Date : 2024-07-26 DOI: 10.1038/s41594-024-01366-8

Jasleen Gill

引用次数: 0

The cyanobacterial protein VIPP1 forms ESCRT-III-like structures on lipid bilayers 蓝藻蛋白 VIPP1 在脂质双分子层上形成类似 ESCRT-III 的结构

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-07-26 DOI: 10.1038/s41594-024-01367-7

Sichen Pan, Karin Gries, Benjamin D. Engel, Michael Schroda, Christoph A. Haselwandter, Simon Scheuring

{"title":"The cyanobacterial protein VIPP1 forms ESCRT-III-like structures on lipid bilayers","authors":"Sichen Pan, Karin Gries, Benjamin D. Engel, Michael Schroda, Christoph A. Haselwandter, Simon Scheuring","doi":"10.1038/s41594-024-01367-7","DOIUrl":"10.1038/s41594-024-01367-7","url":null,"abstract":"The biogenesis and maintenance of thylakoid membranes require vesicle-inducing protein in plastids 1 (VIPP1). VIPP1 is a member of the endosomal sorting complex required for transport-III (ESCRT-III) superfamily, whose members form diverse filament-based supramolecular structures that facilitate membrane deformation and fission. VIPP1 cryo-electron microscopy (EM) structures in solution revealed helical rods and baskets of stacked rings, with amphipathic membrane-binding domains in the lumen. However, how VIPP1 interacts with membranes remains largely unknown. Here, using high-speed atomic force microscopy (HS-AFM), we show that VIPP1 assembles into right-handed chiral spirals and regular polygons on supported lipid bilayers via ESCRT-III-like filament assembly and dynamics. VIPP1 filaments grow clockwise into spirals through polymerization at a ring-shaped central polymerization hub, and into polygons through clockwise polymerization at the sector peripheries. Interestingly, VIPP1 initially forms Archimedean spirals, which upon maturation transform into logarithmic spirals through lateral annealing of strands to the outermore low-curvature spiral turns. Using high-speed atomic force microscopy, the authors reveal the polymerization mechanism of VIPP1 into ESCRT-III-like filaments that adopt spiral and polygonal supramolecular structures.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"543-554"},"PeriodicalIF":12.5,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764278","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

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

Nature Structural & 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

{"title":"Poised PABP–RNA hubs implement signal-dependent mRNA decay in development","authors":"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","doi":"10.1038/s41594-024-01363-x","DOIUrl":"10.1038/s41594-024-01363-x","url":null,"abstract":"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.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1439-1447"},"PeriodicalIF":12.5,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01363-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759830","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 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

Nature Structural & 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

{"title":"Structural basis for activity switching in polymerases determining the fate of let-7 pre-miRNAs","authors":"Gangshun Yi, Mingda Ye, Loic Carrique, Afaf El-Sagheer, Tom Brown, Chris J. Norbury, Peijun Zhang, Robert J. C. Gilbert","doi":"10.1038/s41594-024-01357-9","DOIUrl":"10.1038/s41594-024-01357-9","url":null,"abstract":"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.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1426-1438"},"PeriodicalIF":12.5,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01357-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759831","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