Nature Structural & Molecular Biology最新文献

{"title":"Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families","authors":"Lily Yeh Jan, Yuh Nung Jan","doi":"10.1038/s41594-024-01444-x","DOIUrl":"10.1038/s41594-024-01444-x","url":null,"abstract":"Calcium (Ca2+)-activated ion channels and lipid scramblases in the transmembrane protein 16 (TMEM16) family are structurally related to mechanosensitive ion channels in the TMEM63 and transmembrane channel-like (TMC) families. Members of this structurally related superfamily share similarities in gating transitions and serve a wide range of physiological functions, which is evident from their disease associations. The TMEM16, TMEM63 and TMC families include members with important functions in the cell membrane and/or intracellular organelles such as the endoplasmic reticulum, membrane contact sites, endosomes and lysosomes. Moreover, some members of the TMEM16 family and the TMC family perform dual functions of ion channel and lipid scramblase, leading to intriguing physiological implications. In addition to their physiological functions such as mediating phosphatidylserine exposure and facilitation of extracellular vesicle generation and cell fusion, scramblases are involved in the entry and replication of enveloped viruses. Comparisons of structurally diverse scramblases may uncover features in the lipid-scrambling mechanisms that are likely shared by scramblases. In this Review, the authors discuss the physiological and biophysical functions of structurally related TMC, TMEM16 and TMEM63 families, with an aim to elucidate the mechanisms that control ion channel gating and mechanisms for scrambling lipids in the lipid membranes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"222-236"},"PeriodicalIF":12.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874436","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":"Balancing reproductive pursuit and visual danger","authors":"Dimitris Typas","doi":"10.1038/s41594-024-01458-5","DOIUrl":"10.1038/s41594-024-01458-5","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"1-1"},"PeriodicalIF":12.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849139","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":"Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues","authors":"Miao Yu, Nathan R. Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U. Gorkin, Yang E. Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D. Schmitt, Yunjiang Qiu, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Ming Hu, Bing Ren","doi":"10.1038/s41594-024-01431-2","DOIUrl":"10.1038/s41594-024-01431-2","url":null,"abstract":"While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases. The authors here show that chromatin interactions during mouse fetal development are spatiotemporally dynamic. Integrating interactomes with other datasets predicts target genes for candidate enhancers and helps interpret noncoding risk variants in the human genome.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"479-490"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01431-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825550","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":"African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1","authors":"Pilar Álvarez Jerez, Peter Wild Crea, Daniel M. Ramos, Emil K. Gustavsson, Mandy Radefeldt, Andrey Damianov, Mary B. Makarious, Oluwadamilola O. Ojo, Kimberley J. Billingsley, Laksh Malik, Kensuke Daida, Sarah Bromberek, Fangle Hu, Zachary Schneider, Aditya L. Surapaneni, Julia Stadler, Mie Rizig, Huw R. Morris, Caroline B. Pantazis, Hampton L. Leonard, Laurel Screven, Yue A. Qi, Mike A. Nalls, Sara Bandres-Ciga, John Hardy, Henry Houlden, Celeste Eng, Esteban González Burchard, Linda Kachuri, Chia-Ho Lin, Douglas L. Black, Global Parkinson’s Genetics Program (GP2), Andrew B. Singleton, Steffen Fischer, Peter Bauer, Xylena Reed, Mina Ryten, Christian Beetz, Michael Ward, Njideka U. Okubadejo, Cornelis Blauwendraat","doi":"10.1038/s41594-024-01423-2","DOIUrl":"10.1038/s41594-024-01423-2","url":null,"abstract":"Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population. Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1955-1963"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01423-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811350","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":"Structural insights into context-dependent inhibitory mechanisms of chloramphenicol in cells","authors":"Liang Xue, Christian M. T. Spahn, Magdalena Schacherl, Julia Mahamid","doi":"10.1038/s41594-024-01441-0","DOIUrl":"10.1038/s41594-024-01441-0","url":null,"abstract":"Ribosome-targeting antibiotics represent an important class of antimicrobial drugs. Chloramphenicol (Cm) is a well-studied ribosomal peptidyl transferase center (PTC) binder and growing evidence suggests that its inhibitory action depends on the sequence of the nascent peptide. How such selective inhibition on the molecular scale manifests on the cellular level remains unclear. Here, we use cryo-electron tomography to analyze the impact of Cm inside the bacterium Mycoplasma pneumoniae. By resolving the Cm-bound ribosomes to 3.0 Å, we elucidate Cm’s coordination with natural nascent peptides and transfer RNAs in the PTC. We find that Cm leads to the accumulation of a number of translation elongation states, indicating ongoing futile accommodation cycles, and to extensive ribosome collisions. We, thus, suggest that, beyond its direct inhibition of protein synthesis, the action of Cm may involve the activation of cellular stress responses. This work exemplifies how in-cell structural biology can expand the understanding of mechanisms of action for extensively studied antibiotics. Xue et al. visualize how the antibiotic chloramphenicol reshapes the translation landscape and induces ribosome collision in bacterial cells, illuminating its context-dependent action across atomic, molecular and cellular scales.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"257-267"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01441-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809684","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":"Visualizing antibiotic action in a pathogenic bacterium at atomic to cellular scale","authors":"","doi":"10.1038/s41594-024-01442-z","DOIUrl":"10.1038/s41594-024-01442-z","url":null,"abstract":"The mechanisms of antibiotic action can be highly context specific. Using in-cell cryo-electron tomography (cryo-ET) of Mycoplasma pneumoniae — a causative agent of respiratory disease — we visualized the context-dependent action of the ribosome-targeting antibiotic chloramphenicol simultaneously at atomic, molecular and cellular levels. This work highlights how in-cell structural biology can expand our understanding of antibiotic mechanisms of action.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"220-221"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809683","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":"30 years of structural and molecular biology and counting","authors":"","doi":"10.1038/s41594-024-01459-4","DOIUrl":"10.1038/s41594-024-01459-4","url":null,"abstract":"As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1811-1811"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01459-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811391","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":"Understanding ubiquitination in neurodevelopment by integrating insights across space and time","authors":"Mateusz C. Ambrozkiewicz, Sonja Lorenz","doi":"10.1038/s41594-024-01422-3","DOIUrl":"10.1038/s41594-024-01422-3","url":null,"abstract":"Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications. In this perspective, the authors showcase the importance and need for additional investigation of the ubiquitin-dependent regulation of neurodevelopment. They then propose interdisciplinary approaches that will allow improved spatiotemporal understanding of this relationship in the context of basic neuroscience and disease.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"14-22"},"PeriodicalIF":12.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763462","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":"Substrate translocation and inhibition in human dicarboxylate transporter NaDC3","authors":"Yan Li, Jinmei Song, Vedrana Mikusevic, Jennifer J. Marden, Alissa Becerril, Huihui Kuang, Bing Wang, William J. Rice, Joseph A. Mindell, Da-Neng Wang","doi":"10.1038/s41594-024-01433-0","DOIUrl":"10.1038/s41594-024-01433-0","url":null,"abstract":"The human high-affinity sodium–dicarboxylate cotransporter (NaDC3) imports various substrates into the cell as tricarboxylate acid cycle intermediates, lipid biosynthesis precursors and signaling molecules. Understanding the cellular signaling process and developing inhibitors require knowledge of the structural basis of the dicarboxylate specificity and inhibition mechanism of NaDC3. To this end, we determined the cryo-electron microscopy structures of NaDC3 in various dimers, revealing the protomer in three conformations: outward-open Co, outward-occluded Coo and inward-open Ci. A dicarboxylate is first bound and recognized in Co and how the substrate interacts with NaDC3 in Coo likely helps to further determine the substrate specificity. A phenylalanine from the scaffold domain interacts with the bound dicarboxylate in the Coo state and modulates the kinetic barrier to the transport domain movement. Structural comparison of an inhibitor-bound structure of NaDC3 to that of the sodium-dependent citrate transporter suggests ways for making an inhibitor that is specific for NaDC3. The authors show cryo-electron microscopy structures of the human high-affinity sodium–dicarboxylate cotransporter, responsible for dicarboxylate import into the cell, in complex with various substrates and in different states establish the basis of substrate recognition, differentiation and release, as well as regulation of transport domain movement.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"502-512"},"PeriodicalIF":12.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758274","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":"Supporting structural biologists in Africa requires resources and capacity building","authors":"Emmanuel Nji, Aurélien F. A. Moumbock, Katharina C. Cramer, Nicolas V. Rüffin, Jamaine Davis, Oluwatoyin A. Asojo, Julia J. Griese, Amma A. Larbi, Michel N. Fodje","doi":"10.1038/s41594-024-01438-9","DOIUrl":"10.1038/s41594-024-01438-9","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1814-1815"},"PeriodicalIF":12.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753750","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}