Nature Structural & Molecular Biology最新文献

{"title":"Binding of heterochromatin protein Rhino to a subset of piRNA clusters depends on a combination of two histone marks","authors":"Abdou Akkouche, Emma Kneuss, Susanne Bornelöv, Yoan Renaud, Evelyn L. Eastwood, Jasper van Lopik, Nathalie Gueguen, Mingxuan Jiang, Pau Creixell, Stéphanie Maupetit-Mehouas, Anna Sobieszek, Yifan Gui, Benjamin Czech Nicholson, Emilie Brasset, Gregory J. Hannon","doi":"10.1038/s41594-025-01584-8","DOIUrl":"10.1038/s41594-025-01584-8","url":null,"abstract":"Animal germ cells deploy a specialized small RNA-based silencing system, called the PIWI-interacting RNA (piRNA) pathway, to prevent unwanted expression of transposable elements (TEs) and maintain genome integrity. In Drosophila melanogaster germ cells, the majority of piRNA populations originate from dual-strand piRNA clusters, genomic regions highly enriched in TE fragments, via an elaborate machinery centered on the Heterochromatin Protein 1 homolog, Rhino. Although Rhino binds to peptides carrying tri-methylated H3K9 in vitro, it is not fully understood why in vivo only a fraction of H3K9me3-decorated heterochromatin is occupied by Rhino. Recent work revealed that Rhino is recruited to a subset of piRNA clusters by Kipferl. Here we identify a Kipferl-independent mode of Rhino recruitment that, in addition to the previously established role of H3K9me3, also depends on the histone H3 lysine 27 methyltransferase Enhancer of Zeste. At Kipferl-independent sites, we find that Rhino specifically binds to loci marked by both H3K9me3 and H3K27me3 via its chromodomain. Although the exact mechanism of how Rhino binding is influenced by dual histone modifications remains unclear from a structural and biochemical perspective, our work suggests that combinatorial modifications may regulate the specificity of chromatin-binding protein interactions. These findings provide an enhanced understanding of how Rhino targets piRNA source loci, highlighting the sophisticated epigenetic landscape governing TE silencing in Drosophila germ cells. The authors reveal that, in fruit fly ovaries, the protein Rhino is guided to specific regions of the genome by a combination of two histone modifications, enhancing understanding of how cells protect their DNA from harmful virus-like elements.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1517-1527"},"PeriodicalIF":10.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01584-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305383","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":"H3K27me3 expands the epigenetic control of piRNA transcription","authors":"Arantxa M. L. Rojas, Germano Cecere","doi":"10.1038/s41594-025-01572-y","DOIUrl":"10.1038/s41594-025-01572-y","url":null,"abstract":"Constitutive heterochromatin can promote piRNA transcription, a crucial step in genome defense. Two studies now show that piRNA transcription in Drosophila is regulated by the dual histone marks H3K27me3 and H3K9me3, and piRNA transcription in Caenorhabditis elegans is enhanced by H3K27me3, gene clustering and phase separation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1322-1324"},"PeriodicalIF":10.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305382","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":"UFMylation-dependent quality control of ER-stalled ribosomes","authors":"Dimitris Typas","doi":"10.1038/s41594-025-01606-5","DOIUrl":"10.1038/s41594-025-01606-5","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 6","pages":"956-956"},"PeriodicalIF":10.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269173","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":"Better SIFI than sorry","authors":"Sara Osman","doi":"10.1038/s41594-025-01608-3","DOIUrl":"10.1038/s41594-025-01608-3","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 6","pages":"956-956"},"PeriodicalIF":10.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269044","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":"Comprehensive analysis of Saccharomyces cerevisiae intron structures in vivo","authors":"Ramya Rangan, Rui Huang, Oarteze Hunter, Phillip Pham, Manuel Ares Jr., Rhiju Das","doi":"10.1038/s41594-025-01565-x","DOIUrl":"10.1038/s41594-025-01565-x","url":null,"abstract":"Pre-mRNA secondary structures are hypothesized to regulate RNA processing pathways, but such structures have been difficult to visualize in vivo. Here, we characterize Saccharomyces cerevisiae pre-mRNA structures through transcriptome-wide dimethyl sulfate probing, enriching for low-abundance pre-mRNA through splicing inhibition. We cross-validate structures found from phylogenetic and mutational studies and identify structures within the majority of measured introns (79 of 88). We find widespread formation of ‘zipper stems’ between the 5′ splice site and branch point, ‘downstream stems’ between the branch point and the 3′ splice site, and previously uncharacterized long stems that distinguish pre-mRNA from spliced mRNA. Multi-dimensional chemical mapping reveals intron structures that independently form in vitro without the presence of binding partners, and structure ensemble prediction suggests that such structures appear in introns across the Saccharomyces genus. We further develop a high-throughput functional assay to characterize variants of RNA structure (VARS-seq), applying it to 135 sets of stems across 7 introns, identifying structured elements that alter retained intron levels at a distance from canonical splice sites. This transcriptome-wide inference of intron RNA structures introduces alternative paradigms and model systems for understanding how pre-mRNA folding influences gene expression. Here, Rangan et al. characterize S. cerevisiae intron structures with in vivo transcriptome-wide structure probing, showing that certain introns exhibit structural features that distinguish pre-mRNA from spliced mRNA and contain structures that regulate gene expression.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1488-1502"},"PeriodicalIF":10.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01565-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228850","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":"Substrate recognition and allosteric regulation of synaptic vesicle glutamate transporter VGLUT2","authors":"Fei Li, Jacob Eriksen, Juan A. Oses-Prieto, Yessica K. Gomez, Hongfei Xu, Surabhi Hareendranath, Poulomi Das, Janet Finer-Moore, Phuong Nguyen, Alisa Bowen, Andrew Nelson, Alma Burlingame, Michael Grabe, Robert M. Stroud, Robert H. Edwards","doi":"10.1038/s41594-025-01568-8","DOIUrl":"10.1038/s41594-025-01568-8","url":null,"abstract":"The concentration of neurotransmitters inside synaptic vesicles (SVs) underlies the quantal nature of synaptic transmission. Uptake of glutamate, the principal excitatory neurotransmitter, is driven by membrane potential. To prevent nonquantal efflux of glutamate after SV exocytosis, the vesicular glutamate transporters (VGLUTs) are allosterically inhibited by the neutral pH of the synaptic cleft. To elucidate the mechanism, we determined high-resolution structures of rat VGLUT2 with a cyclic analog of glutamate. We propose a mechanism of substrate recognition in which a positively charged cytoplasmic vestibule electrostatically attracts the negatively charged substrate. We also identify modification of VGLUT2 by palmitoylation and find that this promotes retrieval of the transporter after exocytosis. The structure also reveals an extensive network of electrostatic interactions that forms the cytoplasmic gate. Functional analysis of a mutant that disrupts the network shows how this cytoplasmic gate confers the allosteric requirement for lumenal H+ required to restrict VGLUT activity to SVs. Guided by a structure of VGLUT2 with substrate, Li et al. identify the mechanisms for selective substrate recognition, a role for lipid modification in limiting axonal dispersion and for the cytoplasmic gate in allosteric regulation by lumenal H+.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1479-1487"},"PeriodicalIF":10.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201962","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":"RNA helicase unravels the secrets of germ granules","authors":"Ekaterina Voronina","doi":"10.1038/s41594-025-01579-5","DOIUrl":"10.1038/s41594-025-01579-5","url":null,"abstract":"Germ granules contribute to the intergenerational transmission of small RNA-mediated silencing in germ cells. A study in Caenorhabditis elegans now investigates the function of the RNA helicase DDX-19 at the interface between the nuclear pore and the cytoplasmic germ granules.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 7","pages":"1130-1131"},"PeriodicalIF":10.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193157","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":"Structural basis of GluK2 kainate receptor activation by a partial agonist","authors":"Guadalupe Segura-Covarrubias, Changping Zhou, Nebojša Bogdanović, Lisa Zhang, Nami Tajima","doi":"10.1038/s41594-025-01566-w","DOIUrl":"10.1038/s41594-025-01566-w","url":null,"abstract":"Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. Despite their critical roles in synaptic signaling and disease, the detailed gating mechanisms of KARs are not completely understood. Here we present cryo-electron microscopy structures of homomeric rat GluK2 KAR in an unliganded apo state and in complexes with a partial agonist, domoate. Partial agonist-bound GluK2 populates multiple conformations, including intermediate and desensitized states. Moreover, we demonstrate that the N-glycans at the amino-terminal domain–ligand binding domain (LBD) interface modulate receptor gating properties by interfering with cation binding at the LBD dimer interface. Together, these results provide insights into the unique gating mechanisms of KARs. Segura-Covarrubias et al. provide structures of kainate-type ionotropic glutamate receptors in ligand-free and partial agonist-bound conformations. They describe a gating switch upon desensitization and the allosteric modulation of N-glycosylation, which interferes with cation binding.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1456-1469"},"PeriodicalIF":10.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164777","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":"Distinct tau filament folds in human MAPT mutants P301L and P301T","authors":"Manuel Schweighauser, Yang Shi, Alexey G. Murzin, Holly J. Garringer, Ruben Vidal, Jill R. Murrell, M. Elena Erro, Harro Seelaar, Isidro Ferrer, John C. van Swieten, Bernardino Ghetti, Sjors H. W. Scheres, Michel Goedert","doi":"10.1038/s41594-025-01575-9","DOIUrl":"10.1038/s41594-025-01575-9","url":null,"abstract":"Mutations in MAPT, the tau gene, give rise to frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), with abundant filamentous tau inclusions in brain cells. Mutations that encode missense variants of residue P301 are the most common and result in the formation of filamentous inclusions made of mutant four-repeat tau. Here we report the cryo-electron microscopy structures of tau filaments from five individuals belonging to three different families with mutation P301L and from one individual from a family with mutation P301T. A distinct three-lobed tau fold resembling the two-layered fold of Pick’s disease was present in the individuals with P301L tau. Two different tau folds were found in the individual with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. Schweighauser, Shi, Murzin and colleagues report cryo-EM structures of tau filaments from individuals with P301L or P301T MAPT mutations. P301L tau filaments adopted a distinct three-lobed fold, while P301T filaments had either a variant of the three-lobed fold or a V-shaped fold.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1470-1478"},"PeriodicalIF":10.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01575-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164780","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":"Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex","authors":"Minghao Chen, Thanh N. Nguyen, Xuefeng Ren, Grace Khuu, Annan S. I. Cook, Yuanchang Zhao, Ahmet Yildiz, Michael Lazarou, James H. Hurley","doi":"10.1038/s41594-025-01557-x","DOIUrl":"10.1038/s41594-025-01557-x","url":null,"abstract":"The Unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, we determined the cryo-electron microscopy structure of the human ULK1C core at amino-acid-level resolution. We also determined a moderate-resolution structure of the ULK1C core in complex with another autophagy core complex, the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). We show that the two complexes coassemble through extensive contacts between the FIP200 scaffold subunit of ULK1C and the VPS15, ATG14 and BECN1 subunits of PI3KC3-C1. The FIP200:ATG13:ULK1 core of ULK1C undergoes a rearrangement from 2:1:1 to 2:2:2 stoichiometry in the presence of PI3KC3-C1. This suggests a structural mechanism for the initiation of autophagy through formation of a ULK1C:PI3KC3-C1 supercomplex and dimerization of ULK1 on the FIP200 scaffold. Autophagy is initiated by the Unc-51-like kinase protein kinase complex (ULK1C) and class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). Here, the authors reveal the structure of the 2:1:1 core of ULK1C and its complex with PI3KC3-C1. ULK1C transitions to a 2:2:2 complex in the presence of PI3KC3-C1, suggesting a mechanism for autophagy induction.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1596-1605"},"PeriodicalIF":10.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01557-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164778","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}