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

TET activity safeguards pluripotency throughout embryonic dormancy TET 活性可在胚胎休眠期保障多能性

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-23 DOI: 10.1038/s41594-024-01313-7

Maximilian Stötzel, Chieh-Yu Cheng, Ibrahim A. IIik, Abhishek Sampath Kumar, Persia Akbari Omgba, Vera A. van der Weijden, Yufei Zhang, Martin Vingron, Alexander Meissner, Tuğçe Aktaş, Helene Kretzmer, Aydan Bulut-Karslioğlu

{"title":"TET activity safeguards pluripotency throughout embryonic dormancy","authors":"Maximilian Stötzel, Chieh-Yu Cheng, Ibrahim A. IIik, Abhishek Sampath Kumar, Persia Akbari Omgba, Vera A. van der Weijden, Yufei Zhang, Martin Vingron, Alexander Meissner, Tuğçe Aktaş, Helene Kretzmer, Aydan Bulut-Karslioğlu","doi":"10.1038/s41594-024-01313-7","DOIUrl":"10.1038/s41594-024-01313-7","url":null,"abstract":"Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET–transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease. Here the authors show that active DNA demethylation and transcription factor occupation at distal regulatory elements is essential for pluripotency maintenance in dormancy conditions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1625-1639"},"PeriodicalIF":12.5,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01313-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085341","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

eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition 在抑制 mTORC1 的过程中，eIF4A1 可增强 LARP1 介导的翻译抑制作用

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-21 DOI: 10.1038/s41594-024-01321-7

Yuichi Shichino, Tomokazu Yamaguchi, Kazuhiro Kashiwagi, Mari Mito, Mari Takahashi, Takuhiro Ito, Nicholas T. Ingolia, Keiji Kuba, Shintaro Iwasaki

{"title":"eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition","authors":"Yuichi Shichino, Tomokazu Yamaguchi, Kazuhiro Kashiwagi, Mari Mito, Mari Takahashi, Takuhiro Ito, Nicholas T. Ingolia, Keiji Kuba, Shintaro Iwasaki","doi":"10.1038/s41594-024-01321-7","DOIUrl":"10.1038/s41594-024-01321-7","url":null,"abstract":"Eukaryotic translation initiation factor (eIF)4A—a DEAD-box RNA-binding protein—plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator. The authors revealed that the general translation factor eIF4A exerts a repressive effect on a subset of mRNAs by enhancing LARP1 and TOP mRNAs during mTORC1 inhibition under stress.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1557-1566"},"PeriodicalIF":12.5,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074146","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

Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution 古老的 TRPM 酶的酶活性和门控耦合及其分子进化

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-21 DOI: 10.1038/s41594-024-01316-4

Yihe Huang, Sushant Kumar, Junuk Lee, Wei Lü, Juan Du

{"title":"Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution","authors":"Yihe Huang, Sushant Kumar, Junuk Lee, Wei Lü, Juan Du","doi":"10.1038/s41594-024-01316-4","DOIUrl":"10.1038/s41594-024-01316-4","url":null,"abstract":"Channel enzymes represent a class of ion channels with enzymatic activity directly or indirectly linked to their channel function. We investigated a TRPM2 chanzyme from choanoflagellates that integrates two seemingly incompatible functions into a single peptide: a channel module activated by ADP-ribose with high open probability and an enzyme module (NUDT9-H domain) consuming ADP-ribose at a remarkably slow rate. Using time-resolved cryogenic-electron microscopy, we captured a complete series of structural snapshots of gating and catalytic cycles, revealing the coupling mechanism between channel gating and enzymatic activity. The slow kinetics of the NUDT9-H enzyme module confers a self-regulatory mechanism: ADPR binding triggers NUDT9-H tetramerization, promoting channel opening, while subsequent hydrolysis reduces local ADPR, inducing channel closure. We further demonstrated how the NUDT9-H domain has evolved from a structurally semi-independent ADP-ribose hydrolase module in early species to a fully integrated component of a gating ring essential for channel activation in advanced species. Using time-resolved cryo-EM, the authors capture complete structural snapshots of the enzymatic cycle coupled with channel gating in a TRPM-type channel enzyme.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1509-1521"},"PeriodicalIF":12.5,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01316-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074084","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

HES4 controls redox balance and supports pyrimidine synthesis and tumor growth HES4 控制氧化还原平衡，支持嘧啶合成和肿瘤生长

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-20 DOI: 10.1038/s41594-024-01310-w

引用次数: 0

To slide or not to slide: key role of the hexasome in chromatin remodeling revealed 滑动与否：揭示六聚体在染色质重塑中的关键作用

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-20 DOI: 10.1038/s41594-024-01278-7

Daniela Rhodes

引用次数: 0

RNAi screens identify HES4 as a regulator of redox balance supporting pyrimidine synthesis and tumor growth RNAi 筛选发现 HES4 是支持嘧啶合成和肿瘤生长的氧化还原平衡调节器

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-20 DOI: 10.1038/s41594-024-01309-3

Jing He, Aoxue Wang, Qin Zhao, Yejun Zou, Zhuo Zhang, Nannan Sha, Guofang Hou, Bei Zhou, Yi Yang, Tao Chen, Yuzheng Zhao, Yuhui Jiang

{"title":"RNAi screens identify HES4 as a regulator of redox balance supporting pyrimidine synthesis and tumor growth","authors":"Jing He, Aoxue Wang, Qin Zhao, Yejun Zou, Zhuo Zhang, Nannan Sha, Guofang Hou, Bei Zhou, Yi Yang, Tao Chen, Yuzheng Zhao, Yuhui Jiang","doi":"10.1038/s41594-024-01309-3","DOIUrl":"10.1038/s41594-024-01309-3","url":null,"abstract":"NADH/NAD+ redox balance is pivotal for cellular metabolism. Systematic identification of NAD(H) redox regulators, although currently lacking, would help uncover unknown effectors critically implicated in the coordination of growth metabolism. In this study, we performed a genome-scale RNA interference (RNAi) screen to globally survey the genes involved in redox modulation and identified the HES family bHLH transcription factor HES4 as a negative regulator of NADH/NAD+ ratio. Functionally, HES4 is shown to be crucial for maintaining mitochondrial electron transport chain (ETC) activity and pyrimidine synthesis. More specifically, HES4 directly represses transcription of SLC44A2 and SDS, thereby inhibiting mitochondrial choline oxidation and cytosolic serine deamination, respectively, which, in turn, ensures coenzyme Q reduction capacity for DHODH-mediated UMP synthesis and serine-derived dTMP production. Accordingly, inhibition of choline oxidation preserves mitochondrial serine catabolism and ETC-coupled redox balance. Furthermore, HES4 protein stability is enhanced under EGFR activation, and increased HES4 levels facilitate EGFR-driven tumor growth and predict poor prognosis of lung adenocarcinoma. These findings illustrate an unidentified mechanism, underlying pyrimidine biosynthesis in the intersection between serine and choline catabolism, and underscore the physiological importance of HES4 in tumor metabolism. The authors identify genes potentially involved in NAD(H) redox modulation and provide insight on major hit HES4, which uses its transcriptional repressive function to drive pyrimidine nucleotide biosynthesis and tumor growth.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1413-1425"},"PeriodicalIF":12.5,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069478","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 and mechanism of lysosome transmembrane acetylation by HGSNAT HGSNAT 对溶酶体跨膜乙酰化的结构和机制

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-20 DOI: 10.1038/s41594-024-01315-5

Ruisheng Xu, Yingjie Ning, Fandong Ren, Chenxia Gu, Zhengjiang Zhu, Xuefang Pan, Alexey V. Pshezhetsky, Jingpeng Ge, Jie Yu

{"title":"Structure and mechanism of lysosome transmembrane acetylation by HGSNAT","authors":"Ruisheng Xu, Yingjie Ning, Fandong Ren, Chenxia Gu, Zhengjiang Zhu, Xuefang Pan, Alexey V. Pshezhetsky, Jingpeng Ge, Jie Yu","doi":"10.1038/s41594-024-01315-5","DOIUrl":"10.1038/s41594-024-01315-5","url":null,"abstract":"Lysosomal transmembrane acetylation of heparan sulfates (HS) is catalyzed by HS acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), whose dysfunction leads to lysosomal storage diseases. The mechanism by which HGSNAT, the sole non-hydrolase enzyme in HS degradation, brings cytosolic acetyl-coenzyme A (Ac-CoA) and lysosomal HS together for N-acyltransferase reactions remains unclear. Here, we present cryogenic-electron microscopy structures of HGSNAT alone, complexed with Ac-CoA and with acetylated products. These structures explain that Ac-CoA binding from the cytosolic side causes dimeric HGSNAT to form a transmembrane tunnel. Within this tunnel, catalytic histidine and asparagine approach the lumen and instigate the transfer of the acetyl group from Ac-CoA to the glucosamine group of HS. Our study unveils a transmembrane acetylation mechanism that may help advance therapeutic strategies targeting lysosomal storage diseases. This study reports the structure of lysosomal N-acetyltransferase HGSNAT providing insights into the mechanism of lysosomal transmembrane acetylation of heparan sulfate required for its catabolism.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1502-1508"},"PeriodicalIF":12.5,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069452","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 RNA world RNA 世界

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-20 DOI: 10.1038/s41594-024-01327-1

引用次数: 0

Unwinding of a eukaryotic origin of replication visualized by cryo-EM 通过低温电子显微镜观察真核生物复制源的开卷过程

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-17 DOI: 10.1038/s41594-024-01280-z

Sarah S. Henrikus, Marta H. Gross, Oliver Willhoft, Thomas Pühringer, Jacob S. Lewis, Allison W. McClure, Julia F. Greiwe, Giacomo Palm, Andrea Nans, John F. X. Diffley, Alessandro Costa

{"title":"Unwinding of a eukaryotic origin of replication visualized by cryo-EM","authors":"Sarah S. Henrikus, Marta H. Gross, Oliver Willhoft, Thomas Pühringer, Jacob S. Lewis, Allison W. McClure, Julia F. Greiwe, Giacomo Palm, Andrea Nans, John F. X. Diffley, Alessandro Costa","doi":"10.1038/s41594-024-01280-z","DOIUrl":"10.1038/s41594-024-01280-z","url":null,"abstract":"To prevent detrimental chromosome re-replication, DNA loading of a double hexamer of the minichromosome maintenance (MCM) replicative helicase is temporally separated from DNA unwinding. Upon S-phase transition in yeast, DNA unwinding is achieved in two steps: limited opening of the double helix and topological separation of the two DNA strands. First, Cdc45, GINS and Polε engage MCM to assemble a double CMGE with two partially separated hexamers that nucleate DNA melting. In the second step, triggered by Mcm10, two CMGEs separate completely, eject the lagging-strand template and cross paths. To understand Mcm10 during helicase activation, we used biochemical reconstitution with cryogenic electron microscopy. We found that Mcm10 splits the double CMGE by engaging the N-terminal homo-dimerization face of MCM. To eject the lagging strand, DNA unwinding is started from the N-terminal side of MCM while the hexamer channel becomes too narrow to harbor duplex DNA. Here the authors used cryogenic electron microscopy and biochemistry to understand how yeast Mcm10 exerts its essential role in DNA replication initiation, finding that it splits the double Cdc45-MCM-GINS-Polε structure. The lagging-strand template is ejected from each MCM ring as the central channel of the helicase becomes too tight to accommodate two DNA strands.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 8","pages":"1265-1276"},"PeriodicalIF":12.5,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01280-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953637","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

The LexA–RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation LexA-RecA* 结构揭示了 SOS 激活的隐秘锁钥机制

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-16 DOI: 10.1038/s41594-024-01317-3

Michael B. Cory, Allen Li, Christina M. Hurley, Peter J. Carman, Ruth A. Pumroy, Zachary M. Hostetler, Ryann M. Perez, Yarra Venkatesh, Xinning Li, Kushol Gupta, E. James Petersson, Rahul M. Kohli

{"title":"The LexA–RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation","authors":"Michael B. Cory, Allen Li, Christina M. Hurley, Peter J. Carman, Ruth A. Pumroy, Zachary M. Hostetler, Ryann M. Perez, Yarra Venkatesh, Xinning Li, Kushol Gupta, E. James Petersson, Rahul M. Kohli","doi":"10.1038/s41594-024-01317-3","DOIUrl":"10.1038/s41594-024-01317-3","url":null,"abstract":"The bacterial SOS response plays a key role in adaptation to DNA damage, including genomic stress caused by antibiotics. SOS induction begins when activated RecA*, an oligomeric nucleoprotein filament that forms on single-stranded DNA, binds to and stimulates autoproteolysis of the repressor LexA. Here, we present the structure of the complete Escherichia coli SOS signal complex, constituting full-length LexA bound to RecA*. We uncover an extensive interface unexpectedly including the LexA DNA-binding domain, providing a new molecular rationale for ordered SOS gene induction. We further find that the interface involves three RecA subunits, with a single residue in the central engaged subunit acting as a molecular key, inserting into an allosteric binding pocket to induce LexA cleavage. Given the pro-mutagenic nature of SOS activation, our structural and mechanistic insights provide a foundation for developing new therapeutics to slow the evolution of antibiotic resistance. Here, using cryo-EM, the authors reveal the mechanism by which RecA filamented on single-stranded DNA binds to and induces LexA cleavage, the key signal governing the bacterial DNA damage response pathway implicated in antibiotic resistance.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1522-1531"},"PeriodicalIF":12.5,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140949446","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