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

Mechanisms for licensing origins of DNA replication in eukaryotic cells 真核细胞DNA复制起源许可机制

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-30 DOI: 10.1038/s41594-025-01587-5

Bruce Stillman, John F. X. Diffley, Janet H. Iwasa

引用次数: 0

Cell cycle regulation has shaped replication origins in budding yeast 细胞周期调节在出芽酵母中形成了复制起源

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-30 DOI: 10.1038/s41594-025-01591-9

Chew Theng Lim, Thomas C. R. Miller, Kang Wei Tan, Saurabh Talele, Anne Early, Philip East, Humberto Sánchez, Nynke H. Dekker, Alessandro Costa, John F. X. Diffley

{"title":"Cell cycle regulation has shaped replication origins in budding yeast","authors":"Chew Theng Lim, Thomas C. R. Miller, Kang Wei Tan, Saurabh Talele, Anne Early, Philip East, Humberto Sánchez, Nynke H. Dekker, Alessandro Costa, John F. X. Diffley","doi":"10.1038/s41594-025-01591-9","DOIUrl":"10.1038/s41594-025-01591-9","url":null,"abstract":"Eukaryotic DNA replication initiates from genomic loci known as origins. At budding yeast origins like ARS1, a double hexamer (DH) of the MCM replicative helicase is assembled by origin recognition complex (ORC), Cdc6 and Cdt1 by sequential hexamer loading from two opposed ORC binding sites. Cyclin-dependent kinase (CDK) inhibits DH assembly, which prevents re-replication by restricting helicase loading to the G1 phase. Here, we show that an intrinsically disordered region (IDR) in the Orc2 subunit promotes interaction between ORC and the first loaded, closed-ring MCM hexamer (the MCM–ORC (MO) intermediate). CDK-dependent phosphorylation of this IDR blocks MO formation and DH assembly. We show that MO stabilizes ORC at lower-affinity binding sites required for second hexamer loading. Origins comprising two high-affinity ORC sites can assemble DH efficiently without MO by independently loading single hexamers. Strikingly, these origins escape CDK inhibition in vitro and in vivo. Our work reveals mechanistic plasticity in MCM loading with implications for understanding how CDK regulation has shaped yeast origin evolution and how natural, strong origins might escape cell cycle regulation. We also identify key steps common to loading pathways, with implications for understanding how MCM is loaded in other eukaryotes. Licensing of eukaryotic origins of replication with MCM double hexamers (DHs) can occur through distinct pathways. Here, Lim et al. show that in yeast, cell cycle-dependent regulation of DH formation by CDK and origin structure have co-evolved.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1697-1707"},"PeriodicalIF":10.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01591-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516134","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 metabolic hub in ciliary and flagellar motion 纤毛和鞭毛运动的代谢中枢

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-27 DOI: 10.1038/s41594-025-01599-1

Zhuang Xiao, Mingxi Liu

引用次数: 0

Mouse radial spoke 3 is a metabolic and regulatory hub in cilia 小鼠径向辐条3是纤毛的代谢和调节中枢

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-27 DOI: 10.1038/s41594-025-01594-6

Yanhe Zhao, Kangkang Song, Amirrasoul Tavakoli, Long Gui, Angeles Fernandez-Gonzalez, Song Zhang, Petras P. Dzeja, S. Alex Mitsialis, Xuewu Zhang, Daniela Nicastro

{"title":"Mouse radial spoke 3 is a metabolic and regulatory hub in cilia","authors":"Yanhe Zhao, Kangkang Song, Amirrasoul Tavakoli, Long Gui, Angeles Fernandez-Gonzalez, Song Zhang, Petras P. Dzeja, S. Alex Mitsialis, Xuewu Zhang, Daniela Nicastro","doi":"10.1038/s41594-025-01594-6","DOIUrl":"10.1038/s41594-025-01594-6","url":null,"abstract":"Cilia are microtubule-based organelles that have important roles in cell sensing, signaling and motility. Recent studies have revealed the atomic structures of many multicomponent ciliary complexes, elucidating their mechanisms of action. However, little is known about the structure, proteome and function of full-length radial spoke 3 (RS3), a conserved complex that transmits mechanochemical signals to coordinate ciliary motility. Here, we combined single-particle cryo-electron microscopy, cryo-electron tomography, proteomic analysis and computational modeling to determine the three-dimensional structure and atomic model of RS3 from mouse respiratory cilia. We reveal all RS3 components, including regulatory and metabolic enzymes such as a protein kinase A subunit, adenylate kinases (AKs) and malate dehydrogenases. Furthermore, we confirm RS3 loss in AK7-deficient mice, which exhibit motility defects. Our findings identify RS3 as an important regulatory and metabolic hub that maintains sufficient adenosine triphosphate for sustained ciliary beating, providing insights into the etiology of ciliopathies. Zhao et al. uncover the protein composition and atomic structure of ciliary radial spoke 3, revealing it as a metabolic hub that regulates ciliary motility, providing insights into ciliary diseases","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1542-1554"},"PeriodicalIF":10.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500548","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

The PURB–HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation PURB-HOTAIR复合体调节p53依赖的启动子特异性转录激活

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-25 DOI: 10.1038/s41594-025-01597-3

Zhangchuan Xia, Ning Kon, Zhenyi Su, Jingjie Yi, Xu Hua, Hui Zhou, Zhiguo Zhang, Wei Gu

{"title":"The PURB–HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation","authors":"Zhangchuan Xia, Ning Kon, Zhenyi Su, Jingjie Yi, Xu Hua, Hui Zhou, Zhiguo Zhang, Wei Gu","doi":"10.1038/s41594-025-01597-3","DOIUrl":"10.1038/s41594-025-01597-3","url":null,"abstract":"p53 executes its diverse functions through different transcriptional targets but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify purine-rich element binding protein B (PURB), a dual DNA/RNA-binding protein, which acts as a transcriptional corepressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers, and its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and MDM2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB–HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets reveals several promoters that may serve as targets for PURB binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of lncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB–HOTAIR complex. Xia et al. show how p53, guided by cis-regulatory sequences and cofactors (purine-rich element binding protein B and HOX transcript antisense RNA), orchestrates promoter-specific transcriptional regulation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1669-1682"},"PeriodicalIF":10.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479105","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

Structure of fungal tRNA ligase Trl1 with RNA reveals conserved substrate-binding principles 真菌tRNA连接酶Trl1与RNA的结构揭示了保守的底物结合原则

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-25 DOI: 10.1038/s41594-025-01589-3

Sandra Köhler, Jürgen Kopp, Satyabrata Maiti, Janusz M. Bujnicki, Jirka Peschek

{"title":"Structure of fungal tRNA ligase Trl1 with RNA reveals conserved substrate-binding principles","authors":"Sandra Köhler, Jürgen Kopp, Satyabrata Maiti, Janusz M. Bujnicki, Jirka Peschek","doi":"10.1038/s41594-025-01589-3","DOIUrl":"10.1038/s41594-025-01589-3","url":null,"abstract":"RNA ligases play a vital role in RNA processing and maturation, including tRNA splicing, RNA repair and the unfolded protein response (UPR). In fungi and plants, the tripartite tRNA ligase Trl1 catalyzes the joining of TSEN-cleaved pre-tRNA exon halves. Trl1 also functions as ligase in the non-conventional HAC1 mRNA splicing during the UPR. The final ligation step is performed by the N-terminal adenylyltransferase domain (ligase; LIG). The spatial arrangement of the exon ends during the ligation reaction has remained elusive. Here we report the crystal structure of Chaetomium thermophilum Trl1-LIG in complex with a tRNA-derived substrate. Our structure represents a snapshot of the activated RNA intermediate and defines the conserved substrate-binding interface. The underlying enzyme-substrate interplay reveals a substrate-binding principle shared by adenylyltransferases. Moreover, we identify the determinants of RNA end specificity as well as the specific roles of Trl1-LIG’s subdomains during ligase activation, substrate binding and phosphoryl transfer. Köhler et al. present the crystal structure of fungal tRNA ligase Trl1-LIG bound to an activated RNA substrate, providing key insights into conserved substrate binding and activation, enzyme specificity and a tRNA substrate coordination model.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1657-1668"},"PeriodicalIF":10.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01589-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478974","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

PEX14 condensates recruit receptor and cargo pairs for peroxisomal protein import PEX14凝聚物招募受体和货物对，用于过氧化物酶体蛋白的进口

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-24 DOI: 10.1038/s41594-025-01601-w

Jianguo Wu, Shupei Lv, Peng Xu, Suyu Yue, Min Zhuang

{"title":"PEX14 condensates recruit receptor and cargo pairs for peroxisomal protein import","authors":"Jianguo Wu, Shupei Lv, Peng Xu, Suyu Yue, Min Zhuang","doi":"10.1038/s41594-025-01601-w","DOIUrl":"10.1038/s41594-025-01601-w","url":null,"abstract":"Peroxisomal proteins are imported into peroxisomes as folded proteins bound to the receptor peroxisomal biogenesis factor 5 (PEX5) through a biomolecular condensate mainly formed by the tyrosine–glycine (YG) repeats in PEX13. PEX14, another essential component of the translocon complex, contributes to this process by interacting with PEX5 and PEX13 through its N-terminal domain. Clinical data suggest that the human PEX14 (hPEX14) C-terminal domain (CTD) is crucial for peroxisomal protein import. Here we analyze the overall structure of the hPEX14 tetramer and demonstrate that hPEX14 CTD undergoes phase separation in vitro. Replacing hPEX14 CTD with other polypeptides capable of forming condensates partially restores peroxisomal protein import. We found that electrostatic interactions and the specific sequence of the CTD are essential for peroxisomal import. hPEX14 and hPEX13 form immiscible condensates and hPEX14 condensates recruit cargoes containing peroxisome-targeting signal 1 (PTS1) or PTS2 in a PEX5-dependent manner. Overall, our study proposes that PEX14 condensates recruit the receptor–cargo complexes for subsequent partitioning into the PEX13 YG phase. Wu et al. shed light on the role of peroxisomal biogenesis factor 14 (PEX14) in peroxisomal protein import. They show that PEX14 condensates recruit the receptor PEX5 loaded with peroxisome-targeting signal 1 (PTS1) clients or PTS2 clients bound to receptor PEX7.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1644-1656"},"PeriodicalIF":10.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370465","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

P-type ATPase magnesium transporter MgtA acts as a dimer p型atp酶镁转运体MgtA作为二聚体

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-23 DOI: 10.1038/s41594-025-01593-7

Rilee Zeinert, Fei Zhou, Pedro Franco, Jonathan Zöller, Zaid K. Madni, Henry Lessen, L. Aravind, Julian D. Langer, Alexander J. Sodt, Gisela Storz, Doreen Matthies

{"title":"P-type ATPase magnesium transporter MgtA acts as a dimer","authors":"Rilee Zeinert, Fei Zhou, Pedro Franco, Jonathan Zöller, Zaid K. Madni, Henry Lessen, L. Aravind, Julian D. Langer, Alexander J. Sodt, Gisela Storz, Doreen Matthies","doi":"10.1038/s41594-025-01593-7","DOIUrl":"10.1038/s41594-025-01593-7","url":null,"abstract":"Magnesium (Mg2+) uptake systems are present in all domains of life, consistent with the vital role of this ion. P-type ATPase Mg2+ importers are required for bacterial growth when Mg2+ is limiting or during pathogenesis. However, insights into their mechanisms of action are missing. Here we solved the cryo-EM structure of the Mg2+ transporter MgtA from Escherichia coli. We obtained high-resolution structures of both homodimeric (2.9 Å) and monomeric (3.6 Å) forms. The dimer structure is formed by multiple contacts between residues in adjacent soluble N and P subdomains. Our structures revealed an ion, assigned as Mg2+, in the transmembrane segment. Moreover, we detected two cytoplasmic ion-binding sites and determined the structure of the N-terminal tail. Sequence conservation, mutagenesis and ATPase assays indicate dimerization, the ion-binding sites and the N-terminal tail facilitate cation transport or serve regulatory roles. Zeinert et al. provide cryo-EM structures of the E. coli Mg2+ importer MgtA: unexpectedly, this P-type ATPase is a dimer with an uncommon transmembrane ion-binding site and knotted N-terminus, which are functionally important features.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1633-1643"},"PeriodicalIF":10.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341289","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

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism ACAD10和ACAD11促进哺乳动物4-羟基酸脂质分解代谢

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-19 DOI: 10.1038/s41594-025-01596-4

Edrees H. Rashan, Abigail K. Bartlett, Daven B. Khana, Jingying Zhang, Raghav Jain, Gina Wade, Luciano A. Abriata, Andrew J. Smith, Zakery N. Baker, Taylor Cook, Alana Caldwell, Autumn R. Chevalier, Patrick Forny, Brian F. Pfleger, Matteo Dal Peraro, Peng Yuan, Daniel Amador-Noguez, Judith A. Simcox, David J. Pagliarini

{"title":"ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism","authors":"Edrees H. Rashan, Abigail K. Bartlett, Daven B. Khana, Jingying Zhang, Raghav Jain, Gina Wade, Luciano A. Abriata, Andrew J. Smith, Zakery N. Baker, Taylor Cook, Alana Caldwell, Autumn R. Chevalier, Patrick Forny, Brian F. Pfleger, Matteo Dal Peraro, Peng Yuan, Daniel Amador-Noguez, Judith A. Simcox, David J. Pagliarini","doi":"10.1038/s41594-025-01596-4","DOIUrl":"10.1038/s41594-025-01596-4","url":null,"abstract":"Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism. Rashan, Bartlett and colleagues show that mammalian 4-hydroxy fatty acids are primarily catabolized by ACAD10 and ACAD11 (atypical mitochondrial and peroxisomal acyl-CoA dehydrogenases, respectively) that use phosphorylation in their reaction mechanisms.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1622-1632"},"PeriodicalIF":10.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01596-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319877","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

Reporting light microscopy data in our pages 报告光显微镜数据在我们的页面

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-06-17 DOI: 10.1038/s41594-025-01605-6

引用次数: 0