Nature Structural & Molecular Biology最新文献

{"title":"Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor","authors":"Hossein Batebi, Guillermo Pérez-Hernández, Sabrina N. Rahman, Baoliang Lan, Antje Kamprad, Mingyu Shi, David Speck, Johanna K. S. Tiemann, Ramon Guixà-González, Franziska Reinhardt, Peter F. Stadler, Makaía M. Papasergi-Scott, Georgios Skiniotis, Patrick Scheerer, Brian K. Kobilka, Jesper M. Mathiesen, Xiangyu Liu, Peter W. Hildebrand","doi":"10.1038/s41594-024-01334-2","DOIUrl":"10.1038/s41594-024-01334-2","url":null,"abstract":"G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound Gs protein (Gs·GDP; hereafter GsGDP) upon coupling to the β2-adrenergic receptor (β2AR) in atomic detail. The binding of GsGDP to the β2AR is followed by long-range allosteric effects that significantly reduce the energy needed for GDP release: the opening of α1-αF helices, the displacement of the αG helix and the opening of the α-helical domain. Signal propagation to the Gs occurs through an extended receptor interface, including a lysine-rich motif at the intracellular end of a kinked transmembrane helix 6, which was confirmed by site-directed mutagenesis and functional assays. From this β2AR–GsGDP intermediate, Gs undergoes an in-plane rotation along the receptor axis to approach the β2AR–Gsempty state. The simulations shed light on how the structural elements at the receptor–G-protein interface may interact to transmit the signal over 30 Å to the nucleotide-binding site. Our analysis extends the current limited view of nucleotide-free snapshots to include additional states and structural features responsible for signaling and G-protein coupling specificity. Using molecular dynamics simulations and functional assays, authors track the structural changes in heterotrimeric G proteins in response to receptor coupling that lead to the ejection of GDP, the rate-limiting step during G-protein activation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1692-1701"},"PeriodicalIF":12.5,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309030","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":"PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis","authors":"Hiroaki Fujita, Yu-ki Tanaka, Seiryo Ogata, Noriyuki Suzuki, Sota Kuno, Uladzimir Barayeu, Takaaki Akaike, Yasumitsu Ogra, Kazuhiro Iwai","doi":"10.1038/s41594-024-01329-z","DOIUrl":"10.1038/s41594-024-01329-z","url":null,"abstract":"Ferroptosis is a form of regulated cell death induced by iron-dependent accumulation of lipid hydroperoxides. Selenoprotein glutathione peroxidase 4 (GPX4) suppresses ferroptosis by detoxifying lipid hydroperoxides via a catalytic selenocysteine (Sec) residue. Sec, the genetically encoded 21st amino acid, is biosynthesized from a reactive selenium donor on its cognate tRNA[Ser]Sec. It is thought that intracellular selenium must be delivered ‘safely’ and ‘efficiently’ by a carrier protein owing to its high reactivity and very low concentrations. Here, we identified peroxiredoxin 6 (PRDX6) as a novel selenoprotein synthesis factor. Loss of PRDX6 decreases the expression of selenoproteins and induces ferroptosis via a reduction in GPX4. Mechanistically, PRDX6 increases the efficiency of intracellular selenium utilization by transferring selenium between proteins within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, leading to efficient synthesis of selenocysteyl-tRNA[Ser]Sec. These findings highlight previously unidentified selenium metabolic systems and provide new insights into ferroptosis. The authors identified PRDX6 as a novel selenoprotein synthesis factor performing an iron-induced ferroptosis screen. They reveal that PRDX6 greatly facilitates selenium utilization for selenoprotein synthesis by acting as a selenide carrier protein.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 8","pages":"1277-1285"},"PeriodicalIF":12.5,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01329-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309010","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":"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":"31 7","pages":"1145-1145"},"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":"31 8","pages":"1152-1153"},"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":"31 8","pages":"1251-1264"},"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":"31 10","pages":"1543-1556"},"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":"Allosteric competition and inhibition in AMPA receptors","authors":"W. Dylan Hale, Alejandra Montaño Romero, Cuauhtemoc U. Gonzalez, Vasanthi Jayaraman, Albert Y. Lau, Richard L. Huganir, Edward C. Twomey","doi":"10.1038/s41594-024-01328-0","DOIUrl":"10.1038/s41594-024-01328-0","url":null,"abstract":"Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases. Using cryo-electron microscopy, the authors reveal the mechanism by which perampanel-like molecules inhibit AMPA receptors. They show that the inhibitors decouple the ligand-binding domain from the ion channel after neurotransmitter binding and outcompete positive modulators.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1669-1679"},"PeriodicalIF":12.5,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01328-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246303","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":"31 10","pages":"1589-1600"},"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":"31 9","pages":"1448-1459"},"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":"31 8","pages":"1150-1151"},"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}