Nature structural & molecular biology最新文献_第5页

Structure of the human K2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site 人类K2P13.1通道的结构揭示了一个亲水的孔限制和脂质辅助因子位点

Nature structural & molecular biology Pub Date : 2025-02-26 DOI: 10.1038/s41594-024-01476-3

Shatabdi Roy-Chowdhury, Seil Jang, Fayal Abderemane-Ali, Fiona Naughton, Michael Grabe, Daniel L. Minor

{"title":"Structure of the human K2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site","authors":"Shatabdi Roy-Chowdhury, Seil Jang, Fayal Abderemane-Ali, Fiona Naughton, Michael Grabe, Daniel L. Minor","doi":"10.1038/s41594-024-01476-3","DOIUrl":"https://doi.org/10.1038/s41594-024-01476-3","url":null,"abstract":"Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K2P13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly understood mechanisms. Here we present cryo-electron microscopy structures of human THIK1 and mutants, revealing a unique two-chamber aqueous inner cavity obstructed by a hydrophilic barrier important for gating, the flow restrictor, and a P1–M4 intersubunit interface lipid at a site, the PUFA site, corresponding to the K2P small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, Kv7.1, reveals a shared modulatory role for the pore domain intersubunit interface, providing a framework for understanding PUFA action on the VGIC superfamily. Our findings reveal the distinct THIK1 architecture, highlight the importance of the P1–M4 interface for K2P control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"83 1 Pt 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495266","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 and function of a broad-range thermal receptor in myriapods 多足类动物大范围热感受器的结构和功能

Nature structural & molecular biology Pub Date : 2025-02-26 DOI: 10.1038/s41594-025-01495-8

Xiaoying Chen, Licheng Yuan, Han Wen, Qingxia Ma, Zhenfeng Deng, Yongan Xu, Zhihao Yao, Yunfei Wang, Shilong Yang, Nannan Su, Fan Yang

引用次数: 0

Cryo-EM structure of the human THIK-1 K2P K+ channel reveals a lower Y gate regulated by lipids and anesthetics 人类 THIK-1 K2P K+ 通道的低温电子显微镜结构揭示了受脂质和麻醉剂调控的下 Y 门

Nature structural & molecular biology Pub Date : 2025-02-26 DOI: 10.1038/s41594-025-01497-6

Karin E. J. Rödström, Bisher Eymsh, Peter Proks, Mehtab S. Hayre, Sönke Cordeiro, Edward Mendez-Otalvaro, Christian Madry, Anna Rowland, Wojciech Kopec, Simon Newstead, Thomas Baukrowitz, Marcus Schewe, Stephen J. Tucker

{"title":"Cryo-EM structure of the human THIK-1 K2P K+ channel reveals a lower Y gate regulated by lipids and anesthetics","authors":"Karin E. J. Rödström, Bisher Eymsh, Peter Proks, Mehtab S. Hayre, Sönke Cordeiro, Edward Mendez-Otalvaro, Christian Madry, Anna Rowland, Wojciech Kopec, Simon Newstead, Thomas Baukrowitz, Marcus Schewe, Stephen J. Tucker","doi":"10.1038/s41594-025-01497-6","DOIUrl":"https://doi.org/10.1038/s41594-025-01497-6","url":null,"abstract":"THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K+ channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer’s disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower ‘Y gate’ that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495270","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

CTCF and cohesin mediate the chromatin–speckle ground-state association CTCF和黏结蛋白介导染色质斑点基态结合

Nature structural & molecular biology Pub Date : 2025-02-25 DOI: 10.1038/s41594-024-01466-5

引用次数: 0

CTCF/RAD21 organize the ground state of chromatin–nuclear speckle association CTCF/RAD21组织染色质-核散斑结合的基态

Nature structural & molecular biology Pub Date : 2025-02-21 DOI: 10.1038/s41594-024-01465-6

Ruofan Yu, Shelby Roseman, Allison P. Siegenfeld, Zachary Gardner, Son C. Nguyen, Khoa A. Tran, Eric F. Joyce, Rajan Jain, Brian B. Liau, Ian D. Krantz, Katherine A. Alexander, Shelley L. Berger

{"title":"CTCF/RAD21 organize the ground state of chromatin–nuclear speckle association","authors":"Ruofan Yu, Shelby Roseman, Allison P. Siegenfeld, Zachary Gardner, Son C. Nguyen, Khoa A. Tran, Eric F. Joyce, Rajan Jain, Brian B. Liau, Ian D. Krantz, Katherine A. Alexander, Shelley L. Berger","doi":"10.1038/s41594-024-01465-6","DOIUrl":"https://doi.org/10.1038/s41594-024-01465-6","url":null,"abstract":"Recent findings indicate that nuclear speckles, a distinct type of nuclear body, interact with certain chromatin regions in a ground state. Here, we report that the chromatin structural factors CTCF and cohesin are required for full ground-state association between DNA and nuclear speckles. We identified a putative speckle-targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin–nuclear speckle association, disruption of which also impaired induction of speckle-associated genes. Depletion of the cohesin-releasing factor WAPL, which stabilizes cohesin on chromatin, resulted in reinforcement of DNA–speckle contacts and enhanced inducibility of speckle-associated genes. Additionally, we observed disruption of chromatin–nuclear speckle association in patient-derived cells with Cornelia de Lange syndrome, a congenital neurodevelopmental disorder involving defective cohesin pathways. In summary, our findings reveal a mechanism for establishing the ground state of chromatin–speckle association and promoting gene inducibility, with relevance to human disease.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462895","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 how DEK nucleosome binding facilitates H3K27 trimethylation in chromatin DEK核小体结合如何促进染色质中H3K27三甲基化的结构见解

Nature structural & molecular biology Pub Date : 2025-02-21 DOI: 10.1038/s41594-025-01493-w

Tomoya Kujirai, Kenta Echigoya, Yusuke Kishi, Mai Saeki, Tomoko Ito, Junko Kato, Lumi Negishi, Hiroshi Kimura, Hiroshi Masumoto, Yoshimasa Takizawa, Yukiko Gotoh, Hitoshi Kurumizaka

引用次数: 0

Haspin kinase binds to a nucleosomal DNA supergroove Haspin激酶与核小体DNA超槽结合

Nature structural & molecular biology Pub Date : 2025-02-20 DOI: 10.1038/s41594-025-01502-y

Chad W. Hicks, Colin R. Gliech, Sanim Rahman, Xiangbin Zhang, Andrew S. Eneim, Stacy J. Vasquez, Andrew J. Holland, Cynthia Wolberger

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Structural insights into TRPV2 modulation by probenecid probenecid对TRPV2调节的结构见解

Nature structural & molecular biology Pub Date : 2025-02-19 DOI: 10.1038/s41594-025-01494-9

Julia A. Rocereta, Toni Sturhahn, Ruth A. Pumroy, Tabea C. Fricke, Christine Herzog, Andreas Leffler, Vera Moiseenkova-Bell

{"title":"Structural insights into TRPV2 modulation by probenecid","authors":"Julia A. Rocereta, Toni Sturhahn, Ruth A. Pumroy, Tabea C. Fricke, Christine Herzog, Andreas Leffler, Vera Moiseenkova-Bell","doi":"10.1038/s41594-025-01494-9","DOIUrl":"https://doi.org/10.1038/s41594-025-01494-9","url":null,"abstract":"The transient receptor potential vanilloid 2 (TRPV2) cation channel is a key player in cardiovascular physiology and pathophysiology. Probenecid (PBC), an FDA-approved uricosuric agent thought to activate TRPV2, has shown promise in enhancing cardiovascular function in both preclinical and clinical studies. Here our electrophysiological data reveal that PBC significantly potentiates rat TRPV2 to known stimuli, and cryo electron microscopy structures show that PBC directly interacts with rat TRPV2 in a previously unidentified intracellular binding pocket. PBC binding at a conserved TRPV2-specific histidine prevents the channel from taking on the inactivated carboxyl-terminal conformation. This effect extends to TRPV1 and TRPV3 channels when glutamine is substituted with histidine at the corresponding position, increasing their sensitivity to PBC. While PBC alone does not induce TRPV2 opening, its combination with 2-aminoethoxydiphenyl borate enables the channel to adopt an intermediate, potentiated state. Our results offer insights into potential therapeutic advancements for TRPV2 through this pocket.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443302","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

Promoter-proximal RNA polymerase II termination regulates transcription during human cell type transition 启动子-近端RNA聚合酶II终止调节人类细胞类型转变过程中的转录

Nature structural & molecular biology Pub Date : 2025-02-11 DOI: 10.1038/s41594-025-01486-9

Kseniia Lysakovskaia, Arjun Devadas, Björn Schwalb, Michael Lidschreiber, Patrick Cramer

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Uncovering protein glycosylation dynamics and heterogeneity using deep quantitative glycoprofiling (DQGlyco) 利用深度定量糖谱分析（DQGlyco）揭示蛋白质糖基化动力学和异质性

Nature structural & molecular biology Pub Date : 2025-02-10 DOI: 10.1038/s41594-025-01485-w

Clément M. Potel, Mira Lea Burtscher, Martin Garrido-Rodriguez, Amber Brauer-Nikonow, Isabelle Becher, Cecile Le Sueur, Athanasios Typas, Michael Zimmermann, Mikhail M. Savitski

{"title":"Uncovering protein glycosylation dynamics and heterogeneity using deep quantitative glycoprofiling (DQGlyco)","authors":"Clément M. Potel, Mira Lea Burtscher, Martin Garrido-Rodriguez, Amber Brauer-Nikonow, Isabelle Becher, Cecile Le Sueur, Athanasios Typas, Michael Zimmermann, Mikhail M. Savitski","doi":"10.1038/s41594-025-01485-w","DOIUrl":"https://doi.org/10.1038/s41594-025-01485-w","url":null,"abstract":"Protein glycosylation regulates essential cellular processes such as signaling, adhesion and cell–cell interactions; however, dysregulated glycosylation is associated with diseases such as cancer. Here we introduce deep quantitative glycoprofiling (DQGlyco), a robust method that integrates high-throughput sample preparation, highly sensitive detection and precise multiplexed quantification to investigate protein glycosylation dynamics at an unprecedented depth. Using DQGlyco, we profiled the mouse brain glycoproteome, identifying 177,198 unique N-glycopeptides—25 times more than previous studies. We quantified glycopeptide changes in human cells treated with a fucosylation inhibitor and characterized surface-exposed glycoforms. Furthermore, we analyzed tissue-specific glycosylation patterns in mice and demonstrated that a defined gut microbiota substantially remodels the mouse brain glycoproteome, shedding light on the link between the gut microbiome and brain protein functions. Additionally, we developed a novel strategy to evaluate glycoform solubility, offering new insights into their biophysical properties. Overall, the in-depth profiling offered by DQGlyco uncovered extensive complexity in glycosylation regulation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375427","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