Nature structural & molecular biology最新文献_第3页

Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides 肝素和肝素样寡糖对α-突触核蛋白淀粉样纤维的时程重塑和病理干预

Nature structural & molecular biology Pub Date : 2024-10-17 DOI: 10.1038/s41594-024-01407-2

Youqi Tao, Peng Xu, Shenqing Zhang, Wei Shangguan, Guang Yang, Kaien Liu, Xiang Li, Yunpeng Sun, Qinyue Zhao, Dan Li, Biao Yu, Cong Liu

{"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":"https://doi.org/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.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"113 1","pages":""},"PeriodicalIF":0.0,"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":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The guanylate-binding protein GBP1 forms a protein coat that enwraps cytosol-invasive bacteria 鸟苷酸结合蛋白 GBP1 形成包裹细胞膜入侵细菌的蛋白外衣

Nature structural & molecular biology Pub Date : 2024-10-15 DOI: 10.1038/s41594-024-01403-6

引用次数: 0

Structural basis of antimicrobial membrane coat assembly by human GBP1 人类 GBP1 装配抗菌膜衣的结构基础

Nature structural & molecular biology Pub Date : 2024-10-11 DOI: 10.1038/s41594-024-01400-9

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

{"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":"https://doi.org/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.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis for Vipp1 membrane binding: from loose coats and carpets to ring and rod assemblies Vipp1 膜结合的结构基础：从松散的外套和地毯到环状和杆状组件

Nature structural & molecular biology Pub Date : 2024-10-08 DOI: 10.1038/s41594-024-01399-z

Benedikt Junglas, David Kartte, Mirka Kutzner, Nadja Hellmann, Ilona Ritter, Dirk Schneider, Carsten Sachse

{"title":"Structural basis for Vipp1 membrane binding: from loose coats and carpets to ring and rod assemblies","authors":"Benedikt Junglas, David Kartte, Mirka Kutzner, Nadja Hellmann, Ilona Ritter, Dirk Schneider, Carsten Sachse","doi":"10.1038/s41594-024-01399-z","DOIUrl":"https://doi.org/10.1038/s41594-024-01399-z","url":null,"abstract":"Vesicle-inducing protein in plastids 1 (Vipp1) is critical for thylakoid membrane biogenesis and maintenance. Although Vipp1 has recently been identified as a member of the endosomal sorting complexes required for transport III superfamily, it is still unknown how Vipp1 remodels membranes. Here, we present cryo-electron microscopy structures of Synechocystis Vipp1 interacting with membranes: seven structures of helical and stacked-ring assemblies at 5–7-Å resolution engulfing membranes and three carpet structures covering lipid vesicles at ~20-Å resolution using subtomogram averaging. By analyzing ten structures of N-terminally truncated Vipp1, we show that helix α0 is essential for membrane tubulation and forms the membrane-anchoring domain of Vipp1. Lastly, using a conformation-restrained Vipp1 mutant, we reduced the structural plasticity of Vipp1 and determined two structures of Vipp1 at 3.0-Å resolution, resolving the molecular details of membrane-anchoring and intersubunit contacts of helix α0. Our data reveal membrane curvature-dependent structural transitions from carpets to rings and rods, some of which are capable of inducing and/or stabilizing high local membrane curvature triggering membrane fusion.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells 中尺度染色质封闭促进了活细胞中先驱转录因子的目标搜索

Nature structural & molecular biology Pub Date : 2024-10-04 DOI: 10.1038/s41594-024-01385-5

Zuhui Wang, Bo Wang, Di Niu, Chao Yin, Ying Bi, Claudia Cattoglio, Kyle M. Loh, Luke D. Lavis, Hao Ge, Wulan Deng

{"title":"Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells","authors":"Zuhui Wang, Bo Wang, Di Niu, Chao Yin, Ying Bi, Claudia Cattoglio, Kyle M. Loh, Luke D. Lavis, Hao Ge, Wulan Deng","doi":"10.1038/s41594-024-01385-5","DOIUrl":"https://doi.org/10.1038/s41594-024-01385-5","url":null,"abstract":"Pioneer transcription factors (PTFs) possess the unique capability to access closed chromatin regions and initiate cell fate changes, yet the underlying mechanisms remain elusive. Here, we characterized the single-molecule dynamics of PTFs targeting chromatin in living cells, revealing a notable ‘confined target search’ mechanism. PTFs such as FOXA1, FOXA2, SOX2, OCT4 and KLF4 sampled chromatin more frequently than non-PTF MYC, alternating between fast free diffusion in the nucleus and slower confined diffusion within mesoscale zones. Super-resolved microscopy showed closed chromatin organized as mesoscale nucleosome-dense domains, confining FOXA2 diffusion locally and enriching its binding. We pinpointed specific histone-interacting disordered regions, distinct from DNA-binding domains, crucial for confined target search kinetics and pioneer activity within closed chromatin. Fusion to other factors enhanced pioneer activity. Kinetic simulations suggested that transient confinement could increase target association rate by shortening search time and binding repeatedly. Our findings illuminate how PTFs recognize and exploit closed chromatin organization to access targets, revealing a pivotal aspect of gene regulation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure of Fanzor2 reveals insights into the evolution of the TnpB superfamily Fanzor2的结构揭示了TnpB超家族进化的奥秘

Nature structural & molecular biology Pub Date : 2024-10-01 DOI: 10.1038/s41594-024-01394-4

Richard D. Schargel, M. Zuhaib Qayyum, Ajay Singh Tanwar, Ravi C. Kalathur, Elizabeth H. Kellogg

引用次数: 0

Structural features within the NORAD long noncoding RNA underlie efficient repression of Pumilio activity NORAD 长非编码 RNA 的结构特征是有效抑制 Pumilio 活性的基础

Nature structural & molecular biology Pub Date : 2024-09-26 DOI: 10.1038/s41594-024-01393-5

Svetlana Farberov, Omer Ziv, Jian You Lau, Rotem Ben-Tov Perry, Yoav Lubelsky, Eric Miska, Grzegorz Kudla, Igor Ulitsky

{"title":"Structural features within the NORAD long noncoding RNA underlie efficient repression of Pumilio activity","authors":"Svetlana Farberov, Omer Ziv, Jian You Lau, Rotem Ben-Tov Perry, Yoav Lubelsky, Eric Miska, Grzegorz Kudla, Igor Ulitsky","doi":"10.1038/s41594-024-01393-5","DOIUrl":"https://doi.org/10.1038/s41594-024-01393-5","url":null,"abstract":"Long noncoding RNAs (lncRNAs) are increasingly appreciated for their important functions in mammalian cells. However, how their functional capacities are encoded in their sequences and manifested in their structures remains largely unknown. Some lncRNAs bind to and modulate the availability of RNA-binding proteins, but the structural principles that underlie this mode of regulation are unknown. The NORAD lncRNA is a known decoy for Pumilio proteins, which modulate the translation and stability of hundreds of messenger RNAs and, consequently, a regulator of genomic stability and aging. Here we probed the RNA structure and long-range RNA–RNA interactions formed by human NORAD inside cells under different stressful conditions. We discovered a highly modular structure consisting of well-defined domains that contribute independently to NORAD function. Following arsenite stress, most structural domains undergo relaxation and form interactions with other RNAs that are targeted to stress granules. We further revealed a unique structural organization that spatially clusters the multiple Pumilio binding sites along NORAD and consequently contributes to the derepression of Pumilio targets. We then applied these structural principles to design an effective artificial decoy for the let-7 microRNA. Our work demonstrates how the sequence of a lncRNA spatially clusters its function into separated domains and how structural principles can be employed for the rational design of lncRNAs with desired activities.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural insights into translocation and tailored synthesis of hyaluronan 透明质酸转运和定制合成的结构性启示

Nature structural & molecular biology Pub Date : 2024-09-25 DOI: 10.1038/s41594-024-01389-1

Ireneusz Górniak, Zachery Stephens, Satchal K. Erramilli, Tomasz Gawda, Anthony A. Kossiakoff, Jochen Zimmer

引用次数: 0

Structural insights into CXCR4 modulation and oligomerization 对 CXCR4 调制和寡聚化的结构见解

Nature structural & molecular biology Pub Date : 2024-09-23 DOI: 10.1038/s41594-024-01397-1

Kei Saotome, Luke L. McGoldrick, Jo-Hao Ho, Trudy F. Ramlall, Sweta Shah, Michael J. Moore, Jee Hae Kim, Raymond Leidich, William C. Olson, Matthew C. Franklin

{"title":"Structural insights into CXCR4 modulation and oligomerization","authors":"Kei Saotome, Luke L. McGoldrick, Jo-Hao Ho, Trudy F. Ramlall, Sweta Shah, Michael J. Moore, Jee Hae Kim, Raymond Leidich, William C. Olson, Matthew C. Franklin","doi":"10.1038/s41594-024-01397-1","DOIUrl":"https://doi.org/10.1038/s41594-024-01397-1","url":null,"abstract":"Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood. Here, we use cryo-electron microscopy to investigate various modes of human CXCR4 regulation. CXCL12 activates CXCR4 by inserting its N terminus deep into the CXCR4 orthosteric pocket. The binding of US Food and Drug Administration-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its complementarity-determining region H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal modes of G-protein-coupled receptor oligomerization. We show that CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"203 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cryo-EM structures of the Spo11 core complex bound to DNA 与 DNA 结合的 Spo11 核心复合物的冷冻电镜结构

Nature structural & molecular biology Pub Date : 2024-09-20 DOI: 10.1038/s41594-024-01382-8

You Yu, Juncheng Wang, Kaixian Liu, Zhi Zheng, Meret Arter, Corentin Claeys Bouuaert, Stephen Pu, Dinshaw J. Patel, Scott Keeney

引用次数: 0