Nature Structural & Molecular Biology最新文献_第5页

Architecture and activation of single-pass transmembrane receptor guanylyl cyclase 单通道跨膜受体鸟苷酸环化酶的结构与激活

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-14 DOI: 10.1038/s41594-024-01426-z

Shian Liu, Alexander M. Payne, Jinan Wang, Lan Zhu, Navid Paknejad, Edward T. Eng, Wei Liu, Yinglong Miao, Richard K. Hite, Xin-Yun Huang

{"title":"Architecture and activation of single-pass transmembrane receptor guanylyl cyclase","authors":"Shian Liu, Alexander M. Payne, Jinan Wang, Lan Zhu, Navid Paknejad, Edward T. Eng, Wei Liu, Yinglong Miao, Richard K. Hite, Xin-Yun Huang","doi":"10.1038/s41594-024-01426-z","DOIUrl":"10.1038/s41594-024-01426-z","url":null,"abstract":"The heart, in addition to its primary role in blood circulation, functions as an endocrine organ by producing cardiac hormone natriuretic peptides. These hormones regulate blood pressure through the single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor 1. The binding of the peptide hormones to the extracellular domain of the receptor activates the intracellular guanylyl cyclase domain of the receptor to produce the second messenger cyclic guanosine monophosphate. Despite their importance, the detailed architecture and domain interactions within full-length GC-A remain elusive. Here we present cryo-electron microscopy structures, functional analyses and molecular dynamics simulations of full-length human GC-A, in both the absence and the presence of atrial natriuretic peptide. The data reveal the architecture of full-length GC-A, highlighting the spatial arrangement of its various functional domains. This insight is crucial for understanding how different parts of the receptor interact and coordinate during activation. The study elucidates the molecular basis of how extracellular signals are transduced across the membrane to activate the intracellular guanylyl cyclase domain. Here the authors show the structures of single-pass transmembrane receptor guanylyl cyclase in both apo and hormone-bound states, advancing our understanding of cross-membrane signaling by single-pass transmembrane receptors.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"469-478"},"PeriodicalIF":12.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610143","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}

引用次数: 0

Menopause age and cancer risk is influenced by rare genetic variants 绝经年龄和癌症风险受罕见基因变异的影响

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-13 DOI: 10.1038/s41594-024-01434-z

Michelle Korda

引用次数: 0

Structure of the yeast ceramide synthase 酵母神经酰胺合成酶的结构

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-11 DOI: 10.1038/s41594-024-01415-2

Jan-Hannes Schäfer, Lena Clausmeyer, Carolin Körner, Bianca M. Esch, Verena N. Wolf, Jennifer Sapia, Yara Ahmed, Stefan Walter, Stefano Vanni, Dovile Januliene, Arne Moeller, Florian Fröhlich

{"title":"Structure of the yeast ceramide synthase","authors":"Jan-Hannes Schäfer, Lena Clausmeyer, Carolin Körner, Bianca M. Esch, Verena N. Wolf, Jennifer Sapia, Yara Ahmed, Stefan Walter, Stefano Vanni, Dovile Januliene, Arne Moeller, Florian Fröhlich","doi":"10.1038/s41594-024-01415-2","DOIUrl":"10.1038/s41594-024-01415-2","url":null,"abstract":"Ceramides are essential lipids involved in forming complex sphingolipids and acting as signaling molecules. They result from the N-acylation of a sphingoid base and a CoA-activated fatty acid, a reaction catalyzed by the ceramide synthase (CerS) family of enzymes. Yet, the precise structural details and catalytic mechanisms of CerSs have remained elusive. Here we used cryo-electron microscopy single-particle analysis to unravel the structure of the yeast CerS complex in both an active and a fumonisin B1-inhibited state. Our results reveal the complex’s architecture as a dimer of Lip1 subunits bound to the catalytic subunits Lag1 and Lac1. Each catalytic subunit forms a hydrophobic crevice connecting the cytosolic site with the intermembrane space. The active site, located centrally in the tunnel, was resolved in a substrate preloaded state, representing one intermediate in ceramide synthesis. Our data provide evidence for competitive binding of fumonisin B1 to the acyl-CoA-binding tunnel. Using cryo-electron microscopy, Schäfer et al. solved the structure of the yeast ceramide synthase complex, consisting of Lip1, Lag1 and Lac1 subunits. They found that fumonisin B1 binds competitively at a key site, suggesting a mechanism for ceramide synthesis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"441-449"},"PeriodicalIF":12.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598313","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}

引用次数: 0

Structural basis of the mechanism and inhibition of a human ceramide synthase 人类神经酰胺合成酶的机制和抑制作用的结构基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-11 DOI: 10.1038/s41594-024-01414-3

Tomas C. Pascoa, Ashley C. W. Pike, Christofer S. Tautermann, Gamma Chi, Michael Traub, Andrew Quigley, Rod Chalk, Saša Štefanić, Sven Thamm, Alexander Pautsch, Elisabeth P. Carpenter, Gisela Schnapp, David B. Sauer

{"title":"Structural basis of the mechanism and inhibition of a human ceramide synthase","authors":"Tomas C. Pascoa, Ashley C. W. Pike, Christofer S. Tautermann, Gamma Chi, Michael Traub, Andrew Quigley, Rod Chalk, Saša Štefanić, Sven Thamm, Alexander Pautsch, Elisabeth P. Carpenter, Gisela Schnapp, David B. Sauer","doi":"10.1038/s41594-024-01414-3","DOIUrl":"10.1038/s41594-024-01414-3","url":null,"abstract":"Ceramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for different acyl-CoA substrates. Ceramide with a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance and liver disease and the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target for obesity-associated disease. Despite their importance, the molecular mechanism underlying ceramide synthesis by CerS enzymes remains poorly understood. Here we report cryo-electron microscopy structures of human CerS6, capturing covalent intermediate and product-bound states. These structures, along with biochemical characterization, reveal that CerS catalysis proceeds through a ping-pong reaction mechanism involving a covalent acyl–enzyme intermediate. Notably, the product-bound structure was obtained upon reaction with the mycotoxin fumonisin B1, yielding insights into its inhibition of CerS. These results provide a framework for understanding CerS function, selectivity and inhibition and open routes for future drug discovery. Pascoa et al. reveal structures of the human ceramide synthase 6 and elucidate the enzyme’s mechanism. Furthermore, the work uncovers the basis of inhibition by the mycotoxin fumonisin B1.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"431-440"},"PeriodicalIF":12.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01414-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598312","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}

引用次数: 0

Mechanism for Vipp1 spiral formation, ring biogenesis, and membrane repair Vipp1 螺旋形成、环状生物生成和膜修复的机制

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-11 DOI: 10.1038/s41594-024-01401-8

Souvik Naskar, Andrea Merino, Javier Espadas, Jayanti Singh, Aurelien Roux, Adai Colom, Harry H. Low

{"title":"Mechanism for Vipp1 spiral formation, ring biogenesis, and membrane repair","authors":"Souvik Naskar, Andrea Merino, Javier Espadas, Jayanti Singh, Aurelien Roux, Adai Colom, Harry H. Low","doi":"10.1038/s41594-024-01401-8","DOIUrl":"10.1038/s41594-024-01401-8","url":null,"abstract":"The ESCRT-III-like protein Vipp1 couples filament polymerization with membrane remodeling. It assembles planar sheets as well as 3D rings and helical polymers, all implicated in mitigating plastid-associated membrane stress. The architecture of Vipp1 planar sheets and helical polymers remains unknown, as do the geometric changes required to transition between polymeric forms. Here we show how cyanobacterial Vipp1 assembles into morphologically-related sheets and spirals on membranes in vitro. The spirals converge to form a central ring similar to those described in membrane budding. Cryo-EM structures of helical filaments reveal a close geometric relationship between Vipp1 helical and planar lattices. Moreover, the helical structures reveal how filaments twist—a process required for Vipp1, and likely other ESCRT-III filaments, to transition between planar and 3D architectures. Overall, our results provide a molecular model for Vipp1 ring biogenesis and a mechanism for Vipp1 membrane stabilization and repair, with implications for other ESCRT-III systems. Using AFM and cryo-EM, the authors investigate how ESCRT-III-like protein Vipp1 transitions between polymorphic forms of planar sheets and helical filaments, providing insights into membrane-repair processes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"571-584"},"PeriodicalIF":12.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01401-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598337","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}

引用次数: 0

Cryo-electron tomography reveals how COPII assembles on cargo-containing membranes 低温电子断层扫描揭示 COPII 如何在含货物的膜上组装

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-07 DOI: 10.1038/s41594-024-01413-4

Euan Pyle, Elizabeth A. Miller, Giulia Zanetti

{"title":"Cryo-electron tomography reveals how COPII assembles on cargo-containing membranes","authors":"Euan Pyle, Elizabeth A. Miller, Giulia Zanetti","doi":"10.1038/s41594-024-01413-4","DOIUrl":"10.1038/s41594-024-01413-4","url":null,"abstract":"Proteins traverse the eukaryotic secretory pathway through membrane trafficking between organelles. The coat protein complex II (COPII) mediates the anterograde transport of newly synthesized proteins from the endoplasmic reticulum, engaging cargoes with a wide range of size and biophysical properties. The native architecture of the COPII coat and how cargo might influence COPII carrier morphology remain poorly understood. Here we reconstituted COPII-coated membrane carriers using purified Saccharomyces cerevisiae proteins and cell-derived microsomes as a native membrane source. Using cryo-electron tomography with subtomogram averaging, we demonstrate that the COPII coat binds cargo and forms largely spherical vesicles from native membranes. We reveal the architecture of the inner and outer coat layers and shed light on how spherical carriers are formed. Our results provide insights into the architecture and regulation of the COPII coat and advance our current understanding of how membrane curvature is generated. The authors reconstituted coat protein complex II vesicles from native membranes and used cryo-electron tomography and subtomogram averaging to reveal the arrangement of inner and outer coat layers on cargo-containing coated vesicles.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"513-519"},"PeriodicalIF":12.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01413-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594710","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}

引用次数: 0

Tubulin acetyltransferases access and modify the microtubule luminal K40 residue through anchors in taxane-binding pockets 微管蛋白乙酰转移酶通过锚定在类黄酮结合袋中来获取和修改微管管腔内的 K40 残基

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-11-04 DOI: 10.1038/s41594-024-01406-3

Jingyi Luo, Wai Hei Lam, Daqi Yu, Victor C. Chao, Marc Nicholas Zopfi, Chen Jing Khoo, Chang Zhao, Shan Yan, Zheng Liu, Xiang David Li, Chaogu Zheng, Yuanliang Zhai, Shih-Chieh Ti

{"title":"Tubulin acetyltransferases access and modify the microtubule luminal K40 residue through anchors in taxane-binding pockets","authors":"Jingyi Luo, Wai Hei Lam, Daqi Yu, Victor C. Chao, Marc Nicholas Zopfi, Chen Jing Khoo, Chang Zhao, Shan Yan, Zheng Liu, Xiang David Li, Chaogu Zheng, Yuanliang Zhai, Shih-Chieh Ti","doi":"10.1038/s41594-024-01406-3","DOIUrl":"10.1038/s41594-024-01406-3","url":null,"abstract":"Acetylation at α-tubulin K40 is the sole post-translational modification preferred to occur inside the lumen of hollow cylindrical microtubules. However, how tubulin acetyltransferases access the luminal K40 in micrometer-long microtubules remains unknown. Here, we use cryo-electron microscopy and single-molecule reconstitution assays to reveal the enzymatic mechanism for tubulin acetyltransferases to modify K40 in the lumen. One tubulin acetyltransferase spans across the luminal lattice, with the catalytic core docking onto two α-tubulins and the enzyme’s C-terminal domain occupying the taxane-binding pockets of two β-tubulins. The luminal accessibility and enzyme processivity of tubulin acetyltransferases are inhibited by paclitaxel, a microtubule-stabilizing chemotherapeutic agent. Characterizations using recombinant tubulins mimicking preacetylated and postacetylated K40 show the crosstalk between microtubule acetylation states and the cofactor acetyl-CoA in enzyme turnover. Our findings provide crucial insights into the conserved multivalent interactions involving α- and β-tubulins to acetylate the confined microtubule lumen. Here, the authors reveal the mechanism by which anchors of a tubulin acetyltransferase in the β-tubulin taxane-binding pockets have critical roles in the enzyme luminal accessibility and processivity to modify α-tubulin K40 in the microtubule lumen.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"358-368"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574465","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}

引用次数: 0

Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel 异构 TRPC1/TRPC4 通道的冷冻电镜结构

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-10-30 DOI: 10.1038/s41594-024-01408-1

Jongdae Won, Jinhyeong Kim, Jinsung Kim, Juyeon Ko, Christine Haewon Park, Byeongseok Jeong, Sang-Eun Lee, Hyeongseop Jeong, Sun-Hong Kim, Hyunwoo Park, Insuk So, Hyung Ho Lee

{"title":"Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel","authors":"Jongdae Won, Jinhyeong Kim, Jinsung Kim, Juyeon Ko, Christine Haewon Park, Byeongseok Jeong, Sang-Eun Lee, Hyeongseop Jeong, Sun-Hong Kim, Hyunwoo Park, Insuk So, Hyung Ho Lee","doi":"10.1038/s41594-024-01408-1","DOIUrl":"10.1038/s41594-024-01408-1","url":null,"abstract":"Transient receptor potential (TRP) ion channels have a crucial role as cellular sensors, mediating diverse physical and chemical stimuli. The formation of heteromeric structures expands the functionality of TRP channels; however, their molecular architecture remains largely unknown. Here we present the cryo-electron microscopy structures of the human TRPC1/TRPC4 heteromer in the apo and antagonist-bound states, both consisting of one TRPC1 subunit and three TRPC4 subunits. The heteromer structure reveals a distinct ion-conduction pathway, including an asymmetrically constricted selectivity filter and an asymmetric lower gate, primarily attributed to the incorporation of TRPC1. Through a structure-guided electrophysiological assay, we show that both the selectivity filter and the lower part of the S6 helix participate in deciding overall preference for permeating monovalent cations. Moreover, we reveal that the introduction of one lysine residue of TRPC1 into the tetrameric central cavity is enough to render one of the most important functional consequences of TRPC heteromerization: reduced calcium permeability. Our results establish a framework for addressing the structure–function relationship of the heteromeric TRP channels. Here the authors present the cryo-EM structures of heteromeric TRPC1/TRPC4 channel and provide structure–function insights into its heteromer-specific properties.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 2","pages":"326-338"},"PeriodicalIF":12.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541576","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}

引用次数: 0

Publisher Correction: Structure and activation of the RING E3 ubiquitin ligase TRIM72 on the membrane 出版商更正：RING E3 泛素连接酶 TRIM72 在膜上的结构和活化。

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-10-28 DOI: 10.1038/s41594-024-01429-w

Si Hoon Park, Juhyun Han, Byung-Cheon Jeong, Ju Han Song, Se Hwan Jang, Hyeongseop Jeong, Bong Heon Kim, Young-Gyu Ko, Zee-Yong Park, Kyung Eun Lee, Jaekyung Hyun, Hyun Kyu Song

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Author Correction: Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis 作者更正：自身免疫性脑炎中抗体介导的 NMDA 受体聚集和内吞的结构基础

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-10-25 DOI: 10.1038/s41594-024-01410-7

Han Wang, Chun Xie, Bo Deng, Jinjun Ding, Na Li, Zengwei Kou, Mengmeng Jin, Jie He, Qinrui Wang, Han Wen, Jinbao Zhang, Qinming Zhou, Sheng Chen, Xiangjun Chen, Ti-Fei Yuan, Shujia Zhu

引用次数: 0