Molecular Cell最新文献_第5页

Tracking the folding of RNA at its birth 追踪RNA诞生时的折叠过程

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-17 DOI: 10.1016/j.molcel.2025.03.022

Jinsong Zhang, Qiangfeng Cliff Zhang

引用次数: 0

Unraveling the proton-sensing mechanisms of G protein-coupled receptors: Insights from cryogenic electron microscopy studies 揭示G蛋白偶联受体的质子感应机制：来自低温电子显微镜研究的见解

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-17 DOI: 10.1016/j.molcel.2025.03.020

Chenyang Xue, Zhongmin Liu

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Tripartite phosphorylation of SPT5 by CDK9 times pause release and tunes elongation rate of RNA polymerase II CDK9对SPT5的三方磷酸化可暂停释放并调节RNA聚合酶II的延伸率

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-17 DOI: 10.1016/j.molcel.2025.03.021

Rui Sun, Robert P. Fisher

{"title":"Tripartite phosphorylation of SPT5 by CDK9 times pause release and tunes elongation rate of RNA polymerase II","authors":"Rui Sun, Robert P. Fisher","doi":"10.1016/j.molcel.2025.03.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.021","url":null,"abstract":"The RNA polymerase II (RNAPII) transcription cycle is regulated throughout its duration by protein phosphorylation. Previously, two regions phosphorylated by cyclin-dependent kinase 9 (CDK9) in elongation factor SPT5—the linker between Kyrpides-Ouzounis-Woese (KOW) x-4 and 5 domains and carboxy-terminal repeat (CTR) 1—were implicated in promoter-proximal pausing and termination, respectively. Here, we show that phosphorylations in the linker, CTR1, and a third region, CTR2, coordinately control pause release, elongation speed, and termination in HCT116 human colon cancer cells. Pausing was unaffected or increased by mutations preventing CTR1 or CTR2 phosphorylation, respectively, but attenuated when both CTRs were mutated. Whereas loss of CTR1 phosphorylation slowed elongation and repressed nascent transcription, simultaneous CTR2 mutation partially reversed both effects. Nevertheless, mutating both CTRs had additive effects on splicing, termination, steady-state mRNA levels, and cell proliferation. Therefore, tripartite SPT5 phosphorylation times pause release and tunes RNAPII elongation rate to ensure productive transcription and cell viability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"43 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841628","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

Now you see me, now you don’t: What and how viral RNAs are detected by cytoplasmic pattern-recognition receptors 现在你看到我了，现在你看不见了：细胞质模式识别受体检测到病毒rna的内容和方式

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-17 DOI: 10.1016/j.molcel.2025.03.019

Raul Andino, Daniel Darling

引用次数: 0

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis 线粒体-细胞器在建立分区代谢平衡过程中的相互作用

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-17 DOI: 10.1016/j.molcel.2025.03.003

Brandon Chen, Costas A. Lyssiotis, Yatrik M. Shah

{"title":"Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis","authors":"Brandon Chen, Costas A. Lyssiotis, Yatrik M. Shah","doi":"10.1016/j.molcel.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.003","url":null,"abstract":"Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841633","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

Phosphorylation-dependent charge blocks regulate the relaxation of nuclear speckle networks 磷酸化依赖的电荷阻滞调节核散斑网络的弛豫

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-14 DOI: 10.1016/j.molcel.2025.03.016

Mengjun Zhang, Zhuang Gu, Yingtian Sun, Yichen Dong, Junlin Chen, Li Shu, Suibin Ma, Jierui Guo, Yuhang Liang, Qingming Qu, Ning Fang, Chuan-Qi Zhong, Yifan Ge, Zhongwen Chen, Shaohui Huang, Xin Zhang, Bo Wang

{"title":"Phosphorylation-dependent charge blocks regulate the relaxation of nuclear speckle networks","authors":"Mengjun Zhang, Zhuang Gu, Yingtian Sun, Yichen Dong, Junlin Chen, Li Shu, Suibin Ma, Jierui Guo, Yuhang Liang, Qingming Qu, Ning Fang, Chuan-Qi Zhong, Yifan Ge, Zhongwen Chen, Shaohui Huang, Xin Zhang, Bo Wang","doi":"10.1016/j.molcel.2025.03.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.016","url":null,"abstract":"Nuclear speckles (NSs) are viscoelastic network fluids formed via phase separation coupled to percolation (PSCP). Intermolecular crosslinks of SRRM2 lead to the emergence of system-spanning networks, although the physicochemical grammar governing SRRM2 PSCP remains poorly decoded. Here, we demonstrate that SRRM2 is extensively phosphorylated within the intrinsically disordered region (IDR), creating alternating charge blocks. We show that this specific charge pattern does not markedly alter the condensation threshold of SRRM2 in cells. Instead, SRRM2 charge blocks intensify intra-network molecular interactions to modulate the material properties of mesoscopic SRRM2 condensates. We further identify casein kinase 2 (CK2) as the upstream enzyme to catalyze SRRM2 phosphorylation. Phosphorylation of SRRM2 IDR by CK2 facilitates NS relaxation, which is associated with enhanced efficiency of mRNA splicing to safeguard genome stability during DNA damage. Our findings reveal important regulatory mechanisms of charge blocks in modulating the material properties and functions of biomolecular condensates in human cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"112 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827136","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

Proton perception and activation of a proton-sensing GPCR 质子感知GPCR的质子感知和激活

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-10 DOI: 10.1016/j.molcel.2025.02.030

Li-Nan Chen, Hui Zhou, Kun Xi, Shizhuo Cheng, Yongfeng Liu, Yifan Fu, Xiangyu Ma, Ping Xu, Su-Yu Ji, Wei-Wei Wang, Dan-Dan Shen, Huibing Zhang, Qingya Shen, Renjie Chai, Min Zhang, Lin Yang, Feng Han, Chunyou Mao, Xiujun Cai, Yan Zhang

{"title":"Proton perception and activation of a proton-sensing GPCR","authors":"Li-Nan Chen, Hui Zhou, Kun Xi, Shizhuo Cheng, Yongfeng Liu, Yifan Fu, Xiangyu Ma, Ping Xu, Su-Yu Ji, Wei-Wei Wang, Dan-Dan Shen, Huibing Zhang, Qingya Shen, Renjie Chai, Min Zhang, Lin Yang, Feng Han, Chunyou Mao, Xiujun Cai, Yan Zhang","doi":"10.1016/j.molcel.2025.02.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.030","url":null,"abstract":"Maintaining pH at cellular, tissular, and systemic levels is essential for human health. Proton-sensing GPCRs regulate physiological and pathological processes by sensing the extracellular acidity. However, the molecular mechanism of proton sensing and activation of these receptors remains elusive. Here, we present cryoelectron microscopy (cryo-EM) structures of human GPR4, a prototypical proton-sensing GPCR, in its inactive and active states. Our studies reveal that three extracellular histidine residues are crucial for proton sensing of human GPR4. The binding of protons induces substantial conformational changes in GPR4’s ECLs, particularly in ECL2, which transforms from a helix-loop to a β-turn-β configuration. This transformation leads to the rearrangements of H-bond network and hydrophobic packing, relayed by non-canonical motifs to accommodate G proteins. Furthermore, the antagonist NE52-QQ57 hinders human GPR4 activation by preventing hydrophobic stacking rearrangement. Our findings provide a molecular framework for understanding the activation mechanism of a human proton-sensing GPCR, aiding future drug discovery.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"39 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814000","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 and biased signaling of proton sensation by GPCRs mediated by extracellular histidine rearrangement 细胞外组氨酸重排介导的GPCRs质子感觉的结构基础和偏置信号

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-10 DOI: 10.1016/j.molcel.2025.03.018

Lulu Guo, Kongkai Zhu, Ya-Ni Zhong, Mingxin Gao, Junyan Liu, Zhimin Qi, Zili Liu, Naikang Rong, Minghui Zhang, Dongfang Li, Qiyue Zhang, Gongming Yang, Xinxin Zhang, Mingyue Zhang, Ning Ding, Yu-qi Ping, Zhao Yang, Peng Xiao, Ming Xia, Xiao Yu, Fan Yang

{"title":"Structural basis and biased signaling of proton sensation by GPCRs mediated by extracellular histidine rearrangement","authors":"Lulu Guo, Kongkai Zhu, Ya-Ni Zhong, Mingxin Gao, Junyan Liu, Zhimin Qi, Zili Liu, Naikang Rong, Minghui Zhang, Dongfang Li, Qiyue Zhang, Gongming Yang, Xinxin Zhang, Mingyue Zhang, Ning Ding, Yu-qi Ping, Zhao Yang, Peng Xiao, Ming Xia, Xiao Yu, Fan Yang","doi":"10.1016/j.molcel.2025.03.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.018","url":null,"abstract":"Proton sensing by G protein-coupled receptors (GPCRs) is crucial in many life activities. However, its underlying mechanism remains unclear. Here, we report 8 cryoelectron microscopy (cryo-EM) structures of human GPR4 and GPR68 at different pH values and in complex with Gs or Gq trimers or in apo state. Structural inspection, structure-based pKa calculations, and mutational and computational analyses revealed that protonation of two conserved extracellular histidines induced polar network formation and other conformational changes to tether 7-transmembrane (TM7) to second extracellular loop (ECL2), and these changes constitute the central mechanisms of proton-induced activation of GPR4 and GPR68. Unexpectedly, proton sensation by specific extracellular histidine determined biased G protein coupling of GPR4. Moreover, GPR68's additional pH-sensing H842.67 enhances its function in a more acidic optimal pH range. The propagation path connecting proton-sensing histidines to the toggle switch was characterized. Collectively, we provide structural insights into the proton sensing, activation, and downstream effector coupling mechanisms of proton-sensing GPCRs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"37 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813999","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

MLKL activity requires a splicing-regulated, druggable intramolecular interaction MLKL的活性需要剪接调节的、可药物化的分子内相互作用

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-09 DOI: 10.1016/j.molcel.2025.03.015

Uris Ros, Veronica Martinez-Osorio, Pedro A. Valiente, Yasmin Abdelwahab, Milos Gojkovic, Raed Shalaby, Silvia Zanna, Julia Saggau, Laurens Wachsmuth, Harshal N. Nemade, Jonathan Zoeller, Hannah Lottermoser, Yu-Guang Chen, Mohamed Ibrahim, Konstantinos Kelepouras, Lazaros Vasilikos, Paula Bedoya, Rafael A. Espiritu, Stefan Müller, Veronika Altmannova, Ana J. García-Sáez

{"title":"MLKL activity requires a splicing-regulated, druggable intramolecular interaction","authors":"Uris Ros, Veronica Martinez-Osorio, Pedro A. Valiente, Yasmin Abdelwahab, Milos Gojkovic, Raed Shalaby, Silvia Zanna, Julia Saggau, Laurens Wachsmuth, Harshal N. Nemade, Jonathan Zoeller, Hannah Lottermoser, Yu-Guang Chen, Mohamed Ibrahim, Konstantinos Kelepouras, Lazaros Vasilikos, Paula Bedoya, Rafael A. Espiritu, Stefan Müller, Veronika Altmannova, Ana J. García-Sáez","doi":"10.1016/j.molcel.2025.03.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.015","url":null,"abstract":"Necroptosis is an inflammatory form of regulated cell death implicated in a range of human pathologies, whose execution depends on the poorly understood pseudokinase mixed lineage kinase domain-like (MLKL). Here, we report that splicing-dependent insertion of a short amino acid sequence in the C-terminal α-helix (Hc) of MLKL abolishes cell killing activity and creates an anti-necroptotic isoform that counteracts cell death induced by the necroptosis-proficient protein in mice and humans. We show that interaction of Hc with a previously unrecognized hydrophobic groove is essential for necroptosis, which we exploited in a strategy to identify small molecules that inhibit MLKL and substantially ameliorate disease in murine models of necroptosis-driven dermatitis and abdominal aortic aneurysm. Thus, alternative splicing of microexons controls the ability of MLKL to undergo an intramolecular rearrangement essential for necroptosis with potential to guide the development of allosteric MLKL inhibitors for the treatment of human disease.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"16 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806108","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

Modulation of protein activity by small RNA base pairing internal to coding sequences 编码序列内部的小RNA碱基配对对蛋白质活性的调节

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-07 DOI: 10.1016/j.molcel.2025.03.014

Narumon Thongdee, Miranda M. Alaniz, Ekaterina Samatova, Aoshu Zhong, Caroline Esnault, Hongen Zhang, Ryan K. Dale, Marina V. Rodnina, Gisela Storz

{"title":"Modulation of protein activity by small RNA base pairing internal to coding sequences","authors":"Narumon Thongdee, Miranda M. Alaniz, Ekaterina Samatova, Aoshu Zhong, Caroline Esnault, Hongen Zhang, Ryan K. Dale, Marina V. Rodnina, Gisela Storz","doi":"10.1016/j.molcel.2025.03.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.014","url":null,"abstract":"Most characterized interactions between bacterial small RNAs (sRNAs) and their target mRNAs occur near ribosome binding sites, resulting in changes in translation initiation or target mRNA decay. To understand the consequences of sRNA pairing internal to coding sequences detected by global RNA-RNA interactome approaches, we examined the impact of sRNA overexpression on seven target proteins. Overexpression of the sRNA led to decreased target protein levels for two pairs, but there were no differences for the others. By further examining ArcZ-ligA and ArcZ-hemK, we discovered that ArcZ pairing with the mRNAs leads to translation pausing and increased protein activity. A ligA point mutation that eliminates sRNA pairing resulted in increased sensitivity to DNA damage, revealing the physiological consequences of the regulation. Thus, regulatory RNA pairing in coding sequences can locally slow translation elongation, likely impacting co-translational protein folding and allowing improved incorporation of co-factors or more optimal folding under specific conditions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789760","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