Nature Structural & Molecular Biology最新文献_第4页

XPD stalled on cross-linked DNA provides insight into damage verification 在交联 DNA 上停滞的 XPD 可深入了解损伤验证情况

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-28 DOI: 10.1038/s41594-024-01323-5

Jochen Kuper, Tamsanqa Hove, Sarah Maidl, Hermann Neitz, Florian Sauer, Maximilian Kempf, Till Schroeder, Elke Greiter, Claudia Höbartner, Caroline Kisker

{"title":"XPD stalled on cross-linked DNA provides insight into damage verification","authors":"Jochen Kuper, Tamsanqa Hove, Sarah Maidl, Hermann Neitz, Florian Sauer, Maximilian Kempf, Till Schroeder, Elke Greiter, Claudia Höbartner, Caroline Kisker","doi":"10.1038/s41594-024-01323-5","DOIUrl":"10.1038/s41594-024-01323-5","url":null,"abstract":"The superfamily 2 helicase XPD is a central component of the general transcription factor II H (TFIIH), which is essential for transcription and nucleotide excision DNA repair (NER). Within these two processes, the helicase function of XPD is vital for NER but not for transcription initiation, where XPD acts only as a scaffold for other factors. Using cryo-EM, we deciphered one of the most enigmatic steps in XPD helicase action: the active separation of double-stranded DNA (dsDNA) and its stalling upon approaching a DNA interstrand cross-link, a highly toxic form of DNA damage. The structure shows how dsDNA is separated and reveals a highly unusual involvement of the Arch domain in active dsDNA separation. Combined with mutagenesis and biochemical analyses, we identified distinct functional regions important for helicase activity. Surprisingly, those areas also affect core TFIIH translocase activity, revealing a yet unencountered function of XPD within the TFIIH scaffold. In summary, our data provide a universal basis for NER bubble formation, XPD damage verification and XPG incision. Here, using cryo-EM and biochemistry, the authors delineate how the XPD helicase unorthodoxly uses its Arch domain to separate double-stranded DNA upon approaching a DNA lesion, promoting our understanding of NER bubble formation and damage verification.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01323-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159521","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 insights into PPP2R5A degradation by HIV-1 Vif 艾滋病毒-1 Vif 对 PPP2R5A 降解的结构性启示

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-24 DOI: 10.1038/s41594-024-01314-6

Yingxia Hu, Krista A. Delviks-Frankenberry, Chunxiang Wu, Fidel Arizaga, Vinay K. Pathak, Yong Xiong

{"title":"Structural insights into PPP2R5A degradation by HIV-1 Vif","authors":"Yingxia Hu, Krista A. Delviks-Frankenberry, Chunxiang Wu, Fidel Arizaga, Vinay K. Pathak, Yong Xiong","doi":"10.1038/s41594-024-01314-6","DOIUrl":"10.1038/s41594-024-01314-6","url":null,"abstract":"HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A–E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif–CBFβ–elongin B–elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif–PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host–virus protein interactions could serve as potential targets for HIV-1 therapeutics. The authors solve a cryo-EM structure of the regulatory subunit of human protein phosphatase 2A in complex with HIV-1 Vif-containing E3 ligase, leading to improvement of our understanding of host–virus protein interactions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092183","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

Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification Tead4 和 Tfap2c 在全能胚胎中产生双能性和双稳态开关，促进稳健的血统多样化

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-24 DOI: 10.1038/s41594-024-01311-9

Meng Zhu, Maciej Meglicki, Adiyant Lamba, Peizhe Wang, Christophe Royer, Karen Turner, Muhammad Abdullah Jauhar, Celine Jones, Tim Child, Kevin Coward, Jie Na, Magdalena Zernicka-Goetz

{"title":"Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification","authors":"Meng Zhu, Maciej Meglicki, Adiyant Lamba, Peizhe Wang, Christophe Royer, Karen Turner, Muhammad Abdullah Jauhar, Celine Jones, Tim Child, Kevin Coward, Jie Na, Magdalena Zernicka-Goetz","doi":"10.1038/s41594-024-01311-9","DOIUrl":"10.1038/s41594-024-01311-9","url":null,"abstract":"The mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency. TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate. Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo. Here the authors identify the transcription factors TFAP2C and TEAD4 as a bistable switch that reconciles into Hippo ON and OFF states, establishing a composite state at the eight-cell stage and critically regulating lineage diversification.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01311-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092133","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 explosive discovery of TNT in early mouse embryos 小鼠早期胚胎中 TNT 的爆炸性发现

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-24 DOI: 10.1038/s41594-024-01304-8

Chad S. Driscoll, Jaehwan Kim, Jason G. Knott

引用次数: 0

The commander complex is the Swiss Army knife of endosomal trafficking 指挥官复合体是内体运输的瑞士军刀

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-05-23 DOI: 10.1038/s41594-024-01326-2

Natalya Leneva, Oleksiy Kovtun

引用次数: 0

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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

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

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