Nature Structural & Molecular Biology最新文献

{"title":"TMEM63B scrambles phospholipids in response to changes in membrane structure","authors":"","doi":"10.1038/s41594-024-01421-4","DOIUrl":"10.1038/s41594-024-01421-4","url":null,"abstract":"Phospholipid distribution across the lipid bilayer of plasma membranes is critical for various cellular functions. A genome-wide screen and structural analysis identified TMEM63B as a membrane structure-responsive lipid scramblase. In response to changes in membrane structure, TMEM63B alters its conformation and translocates phospholipids, thereby controlling plasma membrane lipid distribution.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"10-11"},"PeriodicalIF":12.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489633","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":"DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency","authors":"Julien Richard Albert, Teresa Urli, Ana Monteagudo-Sánchez, Anna Le Breton, Amina Sultanova, Angélique David, Margherita Scarpa, Mathieu Schulz, Maxim V. C. Greenberg","doi":"10.1038/s41594-024-01405-4","DOIUrl":"10.1038/s41594-024-01405-4","url":null,"abstract":"In mammals, 5-methylcytosine (5mC) and Polycomb repressive complex 2 (PRC2)-deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naive pluripotent state, there is massive gain of 5mC concomitantly with restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naive and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. Instead, this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonist Ezhip (encoding EZH inhibitory protein). At the subset of regions where 5mC appears to genuinely supplant H3K27me3, we identified 163 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Using site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. Our study also implies a noncanonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa. Epigenetic modifications of both DNA and histones undergo profound remodeling during early mammalian development. Epigenome editing demonstrates that DNA methylation can impact certain histone marks, helping control proper gene expression dynamics.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"346-357"},"PeriodicalIF":12.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489044","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":"Mechanism of actin filament severing and capping by gelsolin","authors":"Kyle R. Barrie, Grzegorz Rebowski, Roberto Dominguez","doi":"10.1038/s41594-024-01412-5","DOIUrl":"10.1038/s41594-024-01412-5","url":null,"abstract":"Gelsolin is the prototypical member of a family of Ca2+-activated F-actin severing and capping proteins. Here we report structures of Ca2+-bound human gelsolin at the barbed end of F-actin. One structure reveals gelsolin’s six domains (G1G6) and interdomain linkers wrapping around F-actin, while another shows domains G1G3—a fragment observed during apoptosis—binding on both sides of F-actin. Conformational changes that trigger severing occur on one side of F-actin with G1G6 and on both sides with G1G3. Gelsolin remains bound after severing, blocking subunit exchange. The authors use cryo-electron microscopy to reveal two structural states of Ca2+-activated gelsolin bound to the actin filament, illuminating the mechanisms of filament severing and barbed end capping.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"237-242"},"PeriodicalIF":12.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489058","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":"Clamping Pol ε to the leading strand","authors":"Noopur Singh, Erik Johansson","doi":"10.1038/s41594-024-01416-1","DOIUrl":"10.1038/s41594-024-01416-1","url":null,"abstract":"Two recent studies provide structural insights into how human DNA polymerase ε (Pol ε) interacts with PCNA to form a processive holoenzyme on the leading strand. A series of cryo-EM images offer structural information on the proofreading process, showing how DNA is transferred between the polymerase and exonuclease sites in human Pol ε.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1644-1645"},"PeriodicalIF":12.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486677","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":"Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution","authors":"Yugo Miyata, Katsuya Takahashi, Yongchan Lee, Cheryl S. Sultan, Risa Kuribayashi, Masatomo Takahashi, Kosuke Hata, Takeshi Bamba, Yoshihiro Izumi, Kehong Liu, Tomoko Uemura, Norimichi Nomura, So Iwata, Shigekazu Nagata, Tomohiro Nishizawa, Katsumori Segawa","doi":"10.1038/s41594-024-01411-6","DOIUrl":"10.1038/s41594-024-01411-6","url":null,"abstract":"Phospholipids are asymmetrically distributed in the plasma membrane (PM), with phosphatidylcholine and sphingomyelin abundant in the outer leaflet. However, the mechanisms by which their distribution is regulated remain unclear. Here, we show that transmembrane protein 63B (TMEM63B) functions as a membrane structure-responsive lipid scramblase localized at the PM and lysosomes, activating bidirectional lipid translocation upon changes in membrane curvature and thickness. TMEM63B contains two intracellular loops with palmitoylated cysteine residue clusters essential for its scrambling function. TMEM63B deficiency alters phosphatidylcholine and sphingomyelin distributions in the PM. Persons with heterozygous mutations in TMEM63B are known to develop neurodevelopmental disorders. We show that V44M, the most frequent substitution, confers constitutive scramblase activity on TMEM63B, disrupting PM phospholipid asymmetry. We determined the cryo-electron microscopy structures of TMEM63B in its open and closed conformations, uncovering a lipid translocation pathway formed in response to changes in the membrane environment. Together, our results identify TMEM63B as a membrane structure-responsive scramblase that controls PM lipid distribution and we reveal the molecular basis for lipid scrambling and its biological importance. By combining genome-wide clustered regularly interspaced short palindromic repeats with Cas9 screening and cryo-electron microscopy structure analysis, the authors identified transmembrane protein 63B as a lipid scramblase that detects structural changes in the lipid bilayer and scrambles lipids to regulate membrane lipid distributions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"185-198"},"PeriodicalIF":12.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01411-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448322","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":"Mechanism of polyadenylation-independent RNA polymerase II termination","authors":"Srinivasan Rengachari, Thomas Hainthaler, Christiane Oberthuer, Michael Lidschreiber, Patrick Cramer","doi":"10.1038/s41594-024-01409-0","DOIUrl":"10.1038/s41594-024-01409-0","url":null,"abstract":"The mechanisms underlying the initiation and elongation of RNA polymerase II (Pol II) transcription are well-studied, whereas termination remains poorly understood. Here we analyze the mechanism of polyadenylation-independent Pol II termination mediated by the yeast Sen1 helicase. Cryo-electron microscopy structures of two pretermination intermediates show that Sen1 binds to Pol II and uses its adenosine triphosphatase activity to pull on exiting RNA in the 5′ direction. This is predicted to push Pol II forward, induce an unstable hypertranslocated state and destabilize the transcription bubble, thereby facilitating termination. This mechanism of transcription termination may be widely used because it is conceptually conserved in the bacterial transcription system. In this work, the authors report how the termination factor Sen1 interacts with an elongating RNA polymerase II (Pol II) and its nascent transcript to perform termination. Comparison of two pretermination states of Pol II supports a hypertranslocation model of termination.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"339-345"},"PeriodicalIF":12.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01409-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448324","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":"Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides","authors":"Youqi Tao, Peng Xu, Shenqing Zhang, Wei Shangguan, Guang Yang, Kaien Liu, Xiang Li, Yunpeng Sun, Qinyue Zhao, Dan Li, Biao Yu, Cong Liu","doi":"10.1038/s41594-024-01407-2","DOIUrl":"10.1038/s41594-024-01407-2","url":null,"abstract":"Amyloid fibrils represent a pathological state of protein polymer that is closely associated with various neurodegenerative diseases. Polysaccharides have a prominent role in recognizing amyloid fibrils and mediating their pathogenicity. However, the mechanism underlying the amyloid–polysaccharide interaction remains elusive. We also do not know its impact on the structure and pathology of formed fibrils. Here, we used cryo-electron microscopy to analyze the atomic structures of mature α-synuclein (α-syn) fibrils upon binding with polymeric heparin and heparin-like oligosaccharides. The fibril structure, including the helical twist and conformation of α-syn, changed over time upon the binding of heparin but not oligosaccharides. The sulfation pattern and numbers of saccharide units are important for the binding. Similarly, negatively charged biopolymers typically interact with amyloid fibrils, including tau and various α-syn polymorphs, leading to alterations in their conformation. Moreover, we show that heparin-like oligosaccharides can not only block neuronal uptake and propagation of formed α-syn fibrils but also inhibit α-syn fibrillation. This work demonstrates a distinctive activity of heparin and biopolymers in remodeling amyloid fibrils and suggests the pharmaceutical potential of heparin-like oligosaccharides. Here, the authors reveal progressive conformational changes of α-synuclein fibrils upon binding with polysaccharide heparin, suggesting that biopolymers have a crucial role in remodeling the structures and pathological activities of amyloid fibrils.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"369-380"},"PeriodicalIF":12.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444002","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":"Cohesin closes the door on coexpression","authors":"George Andrew S. Inglis","doi":"10.1038/s41594-024-01404-5","DOIUrl":"10.1038/s41594-024-01404-5","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1463-1463"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439142","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 guanylate-binding protein GBP1 forms a protein coat that enwraps cytosol-invasive bacteria","authors":"","doi":"10.1038/s41594-024-01403-6","DOIUrl":"10.1038/s41594-024-01403-6","url":null,"abstract":"GBP1 is an important innate immunity component that contributes to the control of cytosol-invasive bacterial pathogens. Using cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET) and biophysical assays, we show how GBP1 oligomers enwrap and remodel the lipopolysaccharide (LPS)-containing membrane of gram-negative bacterial pathogens.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"8-9"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440693","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 antimicrobial membrane coat assembly by human GBP1","authors":"Tanja Kuhm, Clémence Taisne, Cecilia de Agrela Pinto, Luca Gross, Evdokia A. Giannopoulou, Stefan T. Huber, Els Pardon, Jan Steyaert, Sander J. Tans, Arjen J. Jakobi","doi":"10.1038/s41594-024-01400-9","DOIUrl":"10.1038/s41594-024-01400-9","url":null,"abstract":"Guanylate-binding proteins (GBPs) are interferon-inducible guanosine triphosphate hydrolases (GTPases) mediating host defense against intracellular pathogens. Their antimicrobial activity hinges on their ability to self-associate and coat pathogen-associated compartments or cytosolic bacteria. Coat formation depends on GTPase activity but how nucleotide binding and hydrolysis prime coat formation remains unclear. Here, we report the cryo-electron microscopy structure of the full-length human GBP1 dimer in its guanine nucleotide-bound state and describe the molecular ultrastructure of the GBP1 coat on liposomes and bacterial lipopolysaccharide membranes. Conformational changes of the middle and GTPase effector domains expose the isoprenylated C terminus for membrane association. The α-helical middle domains form a parallel, crossover arrangement essential for coat formation and position the extended effector domain for intercalation into the lipopolysaccharide layer of gram-negative membranes. Nucleotide binding and hydrolysis create oligomeric scaffolds with contractile abilities that promote membrane extrusion and fragmentation. Our data offer a structural and mechanistic framework for understanding GBP1 effector functions in intracellular immunity. Kuhm et al. reveal how human guanylate-binding protein 1 (GBP1) dimers self-associate to coat bacterial pathogens and uncover a guanosine triphosphate hydrolase-dependent membrane-remodeling activity of GBP1 that is crucial for intracellular immunity","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"172-184"},"PeriodicalIF":12.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01400-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405132","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}