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Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating. 二级结构转变和双PIP2结合定义心脏KCNQ1-KCNE1通道门控。
IF 25.9 1区 生物学
Cell Research Pub Date : 2025-10-02 DOI: 10.1038/s41422-025-01182-9
Ling Zhong, Xiaoqing Lin, Xinyu Cheng, Shuangyan Wan, Yaoguang Hua, Weiwei Nan, Bin Hu, Xiangjun Peng, Zihan Zhou, Qiansen Zhang, Huaiyu Yang, Frank Noé, Zhenzhen Yan, Dexiang Jiang, Hangyu Zhang, Fengjiao Liu, Chenxin Xiao, Zhuo Zhou, Yimin Mou, Haijie Yu, Lijuan Ma, Chen Huang, Vincent Kam Wai Wong, Sookja Kim Chung, Bing Shen, Zhi-Hong Jiang, Erwin Neher, Wandi Zhu, Jin Zhang, Panpan Hou
{"title":"Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.","authors":"Ling Zhong, Xiaoqing Lin, Xinyu Cheng, Shuangyan Wan, Yaoguang Hua, Weiwei Nan, Bin Hu, Xiangjun Peng, Zihan Zhou, Qiansen Zhang, Huaiyu Yang, Frank Noé, Zhenzhen Yan, Dexiang Jiang, Hangyu Zhang, Fengjiao Liu, Chenxin Xiao, Zhuo Zhou, Yimin Mou, Haijie Yu, Lijuan Ma, Chen Huang, Vincent Kam Wai Wong, Sookja Kim Chung, Bing Shen, Zhi-Hong Jiang, Erwin Neher, Wandi Zhu, Jin Zhang, Panpan Hou","doi":"10.1038/s41422-025-01182-9","DOIUrl":"https://doi.org/10.1038/s41422-025-01182-9","url":null,"abstract":"<p><p>The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I<sub>Ks</sub>) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 Å) structures of human KCNQ1<sub>APO</sub>, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 linker, maintaining a loop conformation during I<sub>Ks</sub> gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during I<sub>Ks</sub> gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6', stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes I<sub>Ks</sub> function and provides a foundation for developing targeted LQTS therapy.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205680","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
Lineage plasticity and histological transformation: tumor histology as a spectrum. 谱系可塑性和组织学转化:肿瘤组织学作为一个光谱。
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-30 DOI: 10.1038/s41422-025-01180-x
Xiaoling Li,Eric E Gardner,Sonia Molina-Pinelo,Clare Wilhelm,Ping Mu,Álvaro Quintanal-Villalonga
{"title":"Lineage plasticity and histological transformation: tumor histology as a spectrum.","authors":"Xiaoling Li,Eric E Gardner,Sonia Molina-Pinelo,Clare Wilhelm,Ping Mu,Álvaro Quintanal-Villalonga","doi":"10.1038/s41422-025-01180-x","DOIUrl":"https://doi.org/10.1038/s41422-025-01180-x","url":null,"abstract":"Lineage plasticity, the ability of cells to transition to an alternative phenotype as a means for adaptation, is an increasingly recognized mechanism of tumor evolution and a driver of resistance to anticancer therapies. The most extensively described clinical settings impacted by such molecular phenomena include neuroendocrine transformation in androgen receptor-dependent prostate adenocarcinoma, and adenocarcinoma-to-neuroendocrine and adenocarcinoma-to-squamous transdifferentiation in epidermal growth factor receptor-driven lung adenocarcinoma, affecting 10%-20% of patients treated with targeted therapy. Recent analyses of human tumor samples and in vivo models of histological transformation have led to insights into the biology of lineage plasticity, including biomarkers predictive of high risk of transformation. However, no clinically available therapies aimed to prevent or revert plasticity are currently available. In the present review, we will provide a biological and therapeutic overview of the current understanding of common and divergent molecular drivers of neuroendocrine and squamous transdifferentiation in tumors from different origins, including descriptive analysis of previously known and recently described molecular events associated with histological transformation, and propose evidence-based alternative models of transdifferentiation. A clear definition of the commonalities and differences of transforming tumors in different organs and to different histological fates will be important to translate molecular findings to the clinical setting.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"94 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189203","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
Molecular basis of vitamin K-dependent protein γ-glutamyl carboxylation. 维生素k依赖蛋白γ-谷氨酰羧化的分子基础。
IF 25.9 1区 生物学
Cell Research Pub Date : 2025-09-29 DOI: 10.1038/s41422-025-01185-6
Qihang Zhong, Dandan Chen, Jinkun Xu, Yao Li, Wanqiong Yuan, Yan Meng, Qi Wen, Qiwei Ye, Guopeng Wang, Kexin Pan, Chunli Song, Lin Tao, Jie Qiao, Jing Hang
{"title":"Molecular basis of vitamin K-dependent protein γ-glutamyl carboxylation.","authors":"Qihang Zhong, Dandan Chen, Jinkun Xu, Yao Li, Wanqiong Yuan, Yan Meng, Qi Wen, Qiwei Ye, Guopeng Wang, Kexin Pan, Chunli Song, Lin Tao, Jie Qiao, Jing Hang","doi":"10.1038/s41422-025-01185-6","DOIUrl":"https://doi.org/10.1038/s41422-025-01185-6","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184691","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
Self-RNA Rmrp pre-dimerizes TLR3 for immune activation. 自rna Rmrp使TLR3预二聚体参与免疫激活。
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-29 DOI: 10.1038/s41422-025-01184-7
Ailin Han,Richard A Flavell
{"title":"Self-RNA Rmrp pre-dimerizes TLR3 for immune activation.","authors":"Ailin Han,Richard A Flavell","doi":"10.1038/s41422-025-01184-7","DOIUrl":"https://doi.org/10.1038/s41422-025-01184-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"18 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182724","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
Targeting NNMT in fibroblasts reawakens T cells and restores antitumor immunity. 靶向成纤维细胞中的NNMT可唤醒T细胞并恢复抗肿瘤免疫。
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-24 DOI: 10.1038/s41422-025-01181-w
Moumita Sarkar,Yi Jiang,Raghu Kalluri
{"title":"Targeting NNMT in fibroblasts reawakens T cells and restores antitumor immunity.","authors":"Moumita Sarkar,Yi Jiang,Raghu Kalluri","doi":"10.1038/s41422-025-01181-w","DOIUrl":"https://doi.org/10.1038/s41422-025-01181-w","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"11 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127102","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
ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly. atp依赖的一维运动通过抑制自发的MDA5丝组装来维持免疫稳态。
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-19 DOI: 10.1038/s41422-025-01183-8
Xiao-Peng Han,Ming Rao,Yu Chang,Jun-Yan Zhu,Jun Cheng,Yu-Ting Li,Wu Qiong,Si-Chao Ye,Qiurong Zhang,Shao-Qing Zhang,Ling-Ling Chen,Fajian Hou,Jin Zhong,Jiaquan Liu
{"title":"ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly.","authors":"Xiao-Peng Han,Ming Rao,Yu Chang,Jun-Yan Zhu,Jun Cheng,Yu-Ting Li,Wu Qiong,Si-Chao Ye,Qiurong Zhang,Shao-Qing Zhang,Ling-Ling Chen,Fajian Hou,Jin Zhong,Jiaquan Liu","doi":"10.1038/s41422-025-01183-8","DOIUrl":"https://doi.org/10.1038/s41422-025-01183-8","url":null,"abstract":"MDA5 is a RIG-I-like receptor (RLR) that recognizes viral double-stranded RNA (dsRNA) to initiate the innate immune response. Its activation requires filament formation along the dsRNA, which triggers the oligomerization of N-terminal caspase activation and recruitment domains. The ATPase activity of MDA5 is critical for immune homeostasis, likely by regulating filament assembly. However, the molecular basis underlying this process remains poorly understood. Here, we show that MDA5 operates as an ATP-hydrolysis-driven motor that translocates along dsRNA in a one-dimensional (1D) manner. Multiple MDA5 motors can cooperatively load onto a single dsRNA, but their movements rarely synchronize, inhibiting spontaneous filament formation and activation. LGP2, a key regulator of MDA5 signaling, recognizes MDA5 motors and blocks their movement, thereby promoting filament assembly through a translocation-directed mechanism. This unique assembly strategy underscores the role of 1D motion in higher-order protein oligomerization and reveals a novel mechanism for maintaining immune homeostasis.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"29 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089897","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
White matter interactome in vascular dementia. 血管性痴呆的白质相互作用。
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-17 DOI: 10.1038/s41422-025-01175-8
Stefan Wendt,Brian A MacVicar
{"title":"White matter interactome in vascular dementia.","authors":"Stefan Wendt,Brian A MacVicar","doi":"10.1038/s41422-025-01175-8","DOIUrl":"https://doi.org/10.1038/s41422-025-01175-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"22 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078225","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
Deconstructing the architecture of memory engrams. 解构记忆印迹的架构。
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-17 DOI: 10.1038/s41422-025-01179-4
Yi Zhong,Bo Lei
{"title":"Deconstructing the architecture of memory engrams.","authors":"Yi Zhong,Bo Lei","doi":"10.1038/s41422-025-01179-4","DOIUrl":"https://doi.org/10.1038/s41422-025-01179-4","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"80 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078206","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
Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis 坏死引发的脱落所产生的可溶性组织因子是导致血栓形成的原因
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-12 DOI: 10.1038/s41422-025-01167-8
Peixing Wan, Swati Choksi, Yeon-Ji Park, Xin Chen, Jiong Yan, Sahar Foroutannejad, Zhaoshan Liu, Jichun Chen, Ross Lake, Chengyu Liu, Zheng-Gang Liu
{"title":"Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis","authors":"Peixing Wan, Swati Choksi, Yeon-Ji Park, Xin Chen, Jiong Yan, Sahar Foroutannejad, Zhaoshan Liu, Jichun Chen, Ross Lake, Chengyu Liu, Zheng-Gang Liu","doi":"10.1038/s41422-025-01167-8","DOIUrl":"https://doi.org/10.1038/s41422-025-01167-8","url":null,"abstract":"<p>Tissue factor (TF) is a cell surface protein critical for normal hemostasis and pathological thrombosis. Necroptosis is a form of regulated necrosis associated with different diseases. Here, we reported the identification of the first functional soluble tissue factor (sTF) in mediating blood coagulation, shed from the membrane full-length TF (flTF) by proteases, ADAMs, during necroptosis. By generating sTF-specific antibody and transgenic mice carrying knockin mutations at the ADAM cleavage site of TF (T211V212 mutated to E211E212), we demonstrated that this sTF is responsible for necroptosis-related thrombosis in inflammation and viral infection mouse models. Importantly, we showed that eliminating necroptosis or the cleavage of the flTF blocked the production of sTF and prevented thrombosis in mice. We also detected sTF in the plasma of human COVID-19 patients and showed that SARS-CoV-2 pseudovirus induced sTF production. Our findings demonstrated that the sTF plays a major role in thrombosis under necroptosis-related pathological conditions and provided a diagnostic marker and potential therapies for treating thrombosis without affecting hemostasis.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"67 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035310","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
An anti-inflammatory autophagic target in chronic diseases 慢性疾病中的抗炎自噬靶点
IF 44.1 1区 生物学
Cell Research Pub Date : 2025-09-11 DOI: 10.1038/s41422-025-01176-7
Prithvi Reddy Akepati, Vojo Deretic
{"title":"An anti-inflammatory autophagic target in chronic diseases","authors":"Prithvi Reddy Akepati, Vojo Deretic","doi":"10.1038/s41422-025-01176-7","DOIUrl":"https://doi.org/10.1038/s41422-025-01176-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"13 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031907","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
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