Nature Structural & Molecular Biology最新文献

{"title":"Author Correction: Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors","authors":"Uriel López-Sánchez, Lachlan Jake Munro, Lucy Kate Ladefoged, Anders Juel Pedersen, Christian Colding Brun, Signe Meisner Lyngby, Delphine Baud, Céline Juillan-Binard, Miriam Grønlund Pedersen, Sarah C. R. Lummis, Benny Bang-Andersen, Birgit Schiøtt, Christophe Chipot, Guy Schoehn, Jacques Neyton, Francois Dehez, Hugues Nury, Anders S. Kristensen","doi":"10.1038/s41594-024-01346-y","DOIUrl":"10.1038/s41594-024-01346-y","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01346-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301055","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}

{"title":"Chemical modifications, ions and water molecules in the sub-2 Å resolution structure of the human 80S ribosome","authors":"","doi":"10.1038/s41594-024-01275-w","DOIUrl":"10.1038/s41594-024-01275-w","url":null,"abstract":"Using next-generation cryo-EM and mass spectrometry, we identified 235 chemical modifications in the sub-2 Å resolution structure of the full human 80S ribosome. The newly identified rRNA modifications were found to create new hydrogen bond patterns for riboses and uridines. Ion visualization revealed that Mg2+-associated water molecules are variably substituted by side chains. This study provides the molecular basis for the stabilization of A–U or A–Ψ base pairs and RNA–protein interactions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141264930","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}

{"title":"The structure of the human 80S ribosome at 1.9 Å resolution reveals the molecular role of chemical modifications and ions in RNA","authors":"Samuel Holvec, Charles Barchet, Antony Lechner, Léo Fréchin, S. Nimali T. De Silva, Isabelle Hazemann, Philippe Wolff, Ottilie von Loeffelholz, Bruno P. Klaholz","doi":"10.1038/s41594-024-01274-x","DOIUrl":"10.1038/s41594-024-01274-x","url":null,"abstract":"The ribosomal RNA of the human protein synthesis machinery comprises numerous chemical modifications that are introduced during ribosome biogenesis. Here we present the 1.9 Å resolution cryo electron microscopy structure of the 80S human ribosome resolving numerous new ribosomal RNA modifications and functionally important ions such as Zn2+, K+ and Mg2+, including their associated individual water molecules. The 2′-O-methylation, pseudo-uridine and base modifications were confirmed by mass spectrometry, resulting in a complete investigation of the >230 sites, many of which could not be addressed previously. They choreograph key interactions within the RNA and at the interface with proteins, including at the ribosomal subunit interfaces of the fully assembled 80S ribosome. Uridine isomerization turns out to be a key mechanism for U–A base pair stabilization in RNA in general. The structural environment of chemical modifications and ions is primordial for the RNA architecture of the mature human ribosome, hence providing a structural framework to address their role in healthy states and in human diseases. The cryo-EM structure of the full 80S human ribosome is presented at 1.9 Å resolution. Numerous new chemical modifications are resolved, resulting in over 230 annotated sites cross-validated by mass spectometry. Ions and water molecules are seen to stabilize the RNA architecture.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141264854","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}

{"title":"Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease","authors":"Vivien Horváth, Raquel Garza, Marie E. Jönsson, Pia A. Johansson, Anita Adami, Georgia Christoforidou, Ofelia Karlsson, Laura Castilla Vallmanya, Symela Koutounidou, Patricia Gerdes, Ninoslav Pandiloski, Christopher H. Douse, Johan Jakobsson","doi":"10.1038/s41594-024-01320-8","DOIUrl":"10.1038/s41594-024-01320-8","url":null,"abstract":"SVA (SINE (short interspersed nuclear element)–VNTR (variable number of tandem repeats)–Alu) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized and how their regulatory impact is constrained by an innate epigenetic defense system. Here the authors elucidate how epigenetic regulation influences the regulatory impact of transposable elements in the human genome using cellular models of the neurodegenerative disease XDP, which is caused by an SVA insertion at the TAF1 locus.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01320-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246269","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}

{"title":"XIST dampens X chromosome activity in a SPEN-dependent manner during early human development","authors":"Charbel Alfeghaly, Gaël Castel, Emmanuel Cazottes, Madeleine Moscatelli, Eva Moinard, Miguel Casanova, Juliette Boni, Kasturi Mahadik, Jenna Lammers, Thomas Freour, Louis Chauviere, Carla Piqueras, Ruben Boers, Joachim Boers, Joost Gribnau, Laurent David, Jean-François Ouimette, Claire Rougeulle","doi":"10.1038/s41594-024-01325-3","DOIUrl":"10.1038/s41594-024-01325-3","url":null,"abstract":"XIST (X-inactive specific transcript) long noncoding RNA (lncRNA) is responsible for X chromosome inactivation (XCI) in placental mammals, yet it accumulates on both X chromosomes in human female preimplantation embryos without triggering X chromosome silencing. The XACT (X-active coating transcript) lncRNA coaccumulates with XIST on active X chromosomes and may antagonize XIST function. Here, we used human embryonic stem cells in a naive state of pluripotency to assess the function of XIST and XACT in shaping the X chromosome chromatin and transcriptional landscapes during preimplantation development. We show that XIST triggers the deposition of polycomb-mediated repressive histone modifications and dampens the transcription of most X-linked genes in a SPEN-dependent manner, while XACT deficiency does not significantly affect XIST activity or X-linked gene expression. Our study demonstrates that XIST is functional before XCI, confirms the existence of a transient process of X chromosome dosage compensation and reveals that XCI and dampening rely on the same set of factors. Using naive human embryonic stem cells as a model for early embryogenesis, the authors report that the XIST (X-inactive specific transcript) long noncoding RNA recruits repressive histone marks and attenuates X chromosome expression before the establishment of X chromosome inactivation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01325-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246284","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}

{"title":"ATG16L1 induces the formation of phagophore-like membrane cups","authors":"Jagan Mohan, Satish B. Moparthi, Christine Girard-Blanc, Daniele Campisi, Stéphane Blanchard, Charlotte Nugues, Sowmya Rama, Audrey Salles, Esthel Pénard, Stéphane Vassilopoulos, Thomas Wollert","doi":"10.1038/s41594-024-01300-y","DOIUrl":"10.1038/s41594-024-01300-y","url":null,"abstract":"The hallmark of non-selective autophagy is the formation of cup-shaped phagophores that capture bulk cytoplasm. The process is accompanied by the conjugation of LC3B to phagophores by an E3 ligase complex comprising ATG12–ATG5 and ATG16L1. Here we combined two complementary reconstitution approaches to reveal the function of LC3B and its ligase complex during phagophore expansion. We found that LC3B forms together with ATG12–ATG5–ATG16L1 a membrane coat that remodels flat membranes into cups that closely resemble phagophores. Mechanistically, we revealed that cup formation strictly depends on a close collaboration between LC3B and ATG16L1. Moreover, only LC3B, but no other member of the ATG8 protein family, promotes cup formation. ATG16L1 truncates that lacked the C-terminal membrane binding domain catalyzed LC3B lipidation but failed to assemble coats, did not promote cup formation and inhibited the biogenesis of non-selective autophagosomes. Our results thus demonstrate that ATG16L1 and LC3B induce and stabilize the characteristic cup-like shape of phagophores. Autophagy degrades cellular waste by engulfing it in phagophore membranes and delivering it to lysosomes for degradation. Here Mohan and colleagues identified a type of membrane coat that assembles on phagophores to guide their expansion.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246273","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}

{"title":"How Mcm10 converts the pre-replication complex into two diverging DNA forks","authors":"","doi":"10.1038/s41594-024-01333-3","DOIUrl":"10.1038/s41594-024-01333-3","url":null,"abstract":"Cryo-electron microscopy (cryo-EM) imaging of DNA replication origin activation explains the role of Mcm10, a minichromosome maintenance (MCM) protein homolog, during initiation. Mcm10 acts as a wedge to split the two MCM hexamers of the activated replicative helicase. Diverging replication forks are then established, with changes in the MCM hexamers that promote the topological separation of two DNA strands.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141182376","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}

{"title":"Building up complexity in structural biology studies","authors":"Eva Nogales","doi":"10.1038/s41594-024-01324-4","DOIUrl":"10.1038/s41594-024-01324-4","url":null,"abstract":"Macromolecules are involved in myriads of interactions that regulate their cellular function. While years of structural biology progress was built by reducing this complexity, a molecular understanding of biological processes requires the characterization of ever larger and more dynamic molecular assemblies. Cryo-electron microscopy is rising to this challenge.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177504","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}

{"title":"A unifying model for membrane protein biogenesis","authors":"Ramanujan S. Hegde, Robert J. Keenan","doi":"10.1038/s41594-024-01296-5","DOIUrl":"10.1038/s41594-024-01296-5","url":null,"abstract":"α-Helical integral membrane proteins comprise approximately 25% of the proteome in all organisms. The membrane proteome is highly diverse, varying in the number, topology, spacing and properties of transmembrane domains. This diversity imposes different constraints on the insertion of different regions of a membrane protein into the lipid bilayer. Here, we present a cohesive framework to explain membrane protein biogenesis, in which different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion. In this model, Oxa1 family proteins insert transmembrane domains flanked by short translocated segments, whereas the SecY channel is required for insertion of transmembrane domains flanked by long translocated segments. Our unifying model rationalizes evolutionary, genetic, biochemical and structural data across organisms and provides a foundation for future mechanistic studies of membrane protein biogenesis. In this Perspective, the authors propose a framework to explain membrane protein biogenesis, wherein different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165362","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}

{"title":"MYC phase separation selectively modulates the transcriptome","authors":"Junjiao Yang, Chan-I Chung, Jessica Koach, Hongjiang Liu, Ambuja Navalkar, Hao He, Zhimin Ma, Qian Zhao, Xiaoyu Yang, Liang He, Tanja Mittag, Yin Shen, William A. Weiss, Xiaokun Shu","doi":"10.1038/s41594-024-01322-6","DOIUrl":"10.1038/s41594-024-01322-6","url":null,"abstract":"Dysregulation and enhanced expression of MYC transcription factors (TFs) including MYC and MYCN contribute to the majority of human cancers. For example, MYCN is amplified up to several hundredfold in high-risk neuroblastoma. The resulting overexpression of N-myc aberrantly activates genes that are not activated at low N-myc levels and drives cell proliferation. Whether increasing N-myc levels simply mediates binding to lower-affinity binding sites in the genome or fundamentally changes the activation process remains unclear. One such activation mechanism that could become important above threshold levels of N-myc is the formation of aberrant transcriptional condensates through phase separation. Phase separation has recently been linked to transcriptional regulation, but the extent to which it contributes to gene activation remains an open question. Here we characterized the phase behavior of N-myc and showed that it can form dynamic condensates that have transcriptional hallmarks. We tested the role of phase separation in N-myc-regulated transcription by using a chemogenetic tool that allowed us to compare non-phase-separated and phase-separated conditions at equivalent N-myc levels, both of which showed a strong impact on gene expression compared to no N-myc expression. Interestingly, we discovered that only a small percentage (<3%) of N-myc-regulated genes is further modulated by phase separation but that these events include the activation of key oncogenes and the repression of tumor suppressors. Indeed, phase separation increases cell proliferation, corroborating the biological effects of the transcriptional changes. However, our results also show that >97% of N-myc-regulated genes are not affected by N-myc phase separation, demonstrating that soluble complexes of TFs with the transcriptional machinery are sufficient to activate transcription. Oncoprotein transcription factor MYC undergoes phase separation, forming transcriptionally active condensates. The chemogenetic tool SPARK-ON reveals that MYC phase separation selectively modulates the transcriptome and promotes cell proliferation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01322-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165114","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}