During early mammalian development, the endoderm germ layer forms the foundation of the respiratory and digestive systems through complex patterning. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our study introduces innovative genetic tracing codes for 14 distinct endodermal regions using novel mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging, we detailed the spatiotemporal and genetic lineage differentiation of the endoderm at single-cell resolution. We discovered an unexpected multipotentiality within early endodermal regions, allowing differentiation into various organ primordia. This research illuminates the complex and underestimated phenomenon where endodermal organs develop from multiple origins, prompting a reevaluation of traditional differentiation models. Our findings advance understanding in developmental biology and have significant implications for regenerative medicine and the development of advanced organoid models, providing insights into the intricate mechanisms that guide organogenesis.
{"title":"Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution","authors":"Ke-Ran Li, Pei-Long Yu, Qi-Qi Zheng, Xin Wang, Xuan Fang, Lin-Chen Li, Cheng-Ran Xu","doi":"10.1016/j.cell.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.012","url":null,"abstract":"During early mammalian development, the endoderm germ layer forms the foundation of the respiratory and digestive systems through complex patterning. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our study introduces innovative genetic tracing codes for 14 distinct endodermal regions using novel mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging, we detailed the spatiotemporal and genetic lineage differentiation of the endoderm at single-cell resolution. We discovered an unexpected multipotentiality within early endodermal regions, allowing differentiation into various organ primordia. This research illuminates the complex and underestimated phenomenon where endodermal organs develop from multiple origins, prompting a reevaluation of traditional differentiation models. Our findings advance understanding in developmental biology and have significant implications for regenerative medicine and the development of advanced organoid models, providing insights into the intricate mechanisms that guide organogenesis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"5 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987034","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}
Pub Date : 2025-01-15DOI: 10.1016/j.cell.2024.12.011
Mykhaylo Usyk, Luke Carlson, Nicolas F. Schlecht, Christopher C. Sollecito, Evan Grassi, Fanua Wiek, Shankar Viswanathan, Howard D. Strickler, Anne Nucci-Sack, Angela Diaz, Robert D. Burk
This study investigated the cervicovaginal microbiome’s (CVM’s) impact on Chlamydia trachomatis (CT) infection among Black and Hispanic adolescent and young adult women. A total of 187 women with incident CT were matched to 373 controls, and the CVM was characterized before, during, and after CT infection. The findings highlight that a specific subtype of bacterial vaginosis (BV), identified from 16S rRNA gene reads using the molBV algorithm and community state type (CST) clustering, is a significant risk factor for CT acquisition. A microbial risk score (MRS) further identified a network of bacterial genera associated with increased CT risk. Post treatment, the CVM associated with CT acquisition re-emerged in a different subset of cases leading to reinfection. Additionally, the analysis showed a connection between post-treatment CVM and the development of pelvic inflammatory disease (PID) and miscarriage, further underscoring the CVM’s contributing role to incident CT natural history and highlighting its consideration as a therapeutic target.
{"title":"Cervicovaginal microbiome and natural history of Chlamydia trachomatis in adolescents and young women","authors":"Mykhaylo Usyk, Luke Carlson, Nicolas F. Schlecht, Christopher C. Sollecito, Evan Grassi, Fanua Wiek, Shankar Viswanathan, Howard D. Strickler, Anne Nucci-Sack, Angela Diaz, Robert D. Burk","doi":"10.1016/j.cell.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.011","url":null,"abstract":"This study investigated the cervicovaginal microbiome’s (CVM’s) impact on <em>Chlamydia trachomatis</em> (CT) infection among Black and Hispanic adolescent and young adult women. A total of 187 women with incident CT were matched to 373 controls, and the CVM was characterized before, during, and after CT infection. The findings highlight that a specific subtype of bacterial vaginosis (BV), identified from 16S rRNA gene reads using the <em>molBV</em> algorithm and community state type (CST) clustering, is a significant risk factor for CT acquisition. A microbial risk score (MRS) further identified a network of bacterial genera associated with increased CT risk. Post treatment, the CVM associated with CT acquisition re-emerged in a different subset of cases leading to reinfection. Additionally, the analysis showed a connection between post-treatment CVM and the development of pelvic inflammatory disease (PID) and miscarriage, further underscoring the CVM’s contributing role to incident CT natural history and highlighting its consideration as a therapeutic target.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"52 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981692","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}
Pub Date : 2025-01-15DOI: 10.1016/j.cell.2024.12.027
Nicola L. Harris, Benjamin J. Marsland
The gut microbiota is a powerful influencer of systemic immunity, with its impact on distal organs like the lungs garnering increasing attention. In this issue of Cell, Burrows et al. report that a gut protozoan plays a key role in shaping the immunological steady state of the lung.
{"title":"The gut-lung axis: Protozoa join the party","authors":"Nicola L. Harris, Benjamin J. Marsland","doi":"10.1016/j.cell.2024.12.027","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.027","url":null,"abstract":"The gut microbiota is a powerful influencer of systemic immunity, with its impact on distal organs like the lungs garnering increasing attention. In this issue of <em>Cell</em>, Burrows et al. report that a gut protozoan plays a key role in shaping the immunological steady state of the lung.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"205 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981689","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}
Pub Date : 2025-01-14DOI: 10.1016/j.cell.2024.12.002
In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.
{"title":"Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies","authors":"","doi":"10.1016/j.cell.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.002","url":null,"abstract":"In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974572","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}
Pub Date : 2025-01-14DOI: 10.1016/j.cell.2024.12.005
Jose Espejo Valle-Inclan, Solange De Noon, Katherine Trevers, Hillary Elrick, Ianthe A.E.M. van Belzen, Sonia Zumalave, Carolin M. Sauer, Mélanie Tanguy, Thomas Butters, Francesc Muyas, Alistair G. Rust, Fernanda Amary, Roberto Tirabosco, Adam Giess, Alona Sosinsky, Greg Elgar, Adrienne M. Flanagan, Isidro Cortés-Ciriano
Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
{"title":"Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution","authors":"Jose Espejo Valle-Inclan, Solange De Noon, Katherine Trevers, Hillary Elrick, Ianthe A.E.M. van Belzen, Sonia Zumalave, Carolin M. Sauer, Mélanie Tanguy, Thomas Butters, Francesc Muyas, Alistair G. Rust, Fernanda Amary, Roberto Tirabosco, Adam Giess, Alona Sosinsky, Greg Elgar, Adrienne M. Flanagan, Isidro Cortés-Ciriano","doi":"10.1016/j.cell.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.005","url":null,"abstract":"Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant <em>TP53</em> inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by <em>TP53</em> mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"22 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975085","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}
Pub Date : 2025-01-09DOI: 10.1016/j.cell.2024.12.006
BoRam Lee, K. Ian White, Michael Socolich, Margaret A. Klureza, Robert Henning, Vukica Srajer, Rama Ranganathan, Doeke R. Hekstra
Understanding protein function would be facilitated by direct, real-time observation of chemical kinetics in the atomic structure. The selectivity filter (SF) of the K+ channel provides an ideal model, catalyzing the dehydration and transport of K+ ions across the cell membrane through a narrow pore. We used a “pump-probe” method called electric-field-stimulated time-resolved X-ray crystallography (EFX) to initiate and observe K+ conduction in the NaK2K channel in both directions on the timescale of the transport process. We observe both known and potentially new features in the high-energy conformations visited along the conduction pathway, including the associated dynamics of protein residues that control selectivity and conduction rate. A single time series of one channel in action shows the orderly appearance of features observed in diverse homologs with diverse methods, arguing for deep conservation of the dynamics underlying the reaction coordinate in this protein family.
{"title":"Direct visualization of electric-field-stimulated ion conduction in a potassium channel","authors":"BoRam Lee, K. Ian White, Michael Socolich, Margaret A. Klureza, Robert Henning, Vukica Srajer, Rama Ranganathan, Doeke R. Hekstra","doi":"10.1016/j.cell.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.006","url":null,"abstract":"Understanding protein function would be facilitated by direct, real-time observation of chemical kinetics in the atomic structure. The selectivity filter (SF) of the K<sup>+</sup> channel provides an ideal model, catalyzing the dehydration and transport of K<sup>+</sup> ions across the cell membrane through a narrow pore. We used a “pump-probe” method called electric-field-stimulated time-resolved X-ray crystallography (EFX) to initiate and observe K<sup>+</sup> conduction in the NaK2K channel in both directions on the timescale of the transport process. We observe both known and potentially new features in the high-energy conformations visited along the conduction pathway, including the associated dynamics of protein residues that control selectivity and conduction rate. A single time series of one channel in action shows the orderly appearance of features observed in diverse homologs with diverse methods, arguing for deep conservation of the dynamics underlying the reaction coordinate in this protein family.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"16 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937033","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}
Pub Date : 2025-01-09DOI: 10.1016/j.cell.2024.11.035
In a recently published article in Device, Saehyun Kim et al. report that selective excitation of bacteria can inhibit their proliferation in an antib…
{"title":"Selective excitation of bacteria enables growth suppression without antibiotics","authors":"","doi":"10.1016/j.cell.2024.11.035","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.035","url":null,"abstract":"In a recently published article in Device, Saehyun Kim et al. report that selective excitation of bacteria can inhibit their proliferation in an antib…","PeriodicalId":9656,"journal":{"name":"Cell","volume":"37 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937032","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}
Pub Date : 2025-01-08DOI: 10.1016/j.cell.2024.11.027
Natalie L. Hauglund, Mie Andersen, Klaudia Tokarska, Tessa Radovanovic, Celia Kjaerby, Frederikke L. Sørensen, Zuzanna Bojarowska, Verena Untiet, Sheyla B. Ballestero, Mie G. Kolmos, Pia Weikop, Hajime Hirase, Maiken Nedergaard
As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.
{"title":"Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep","authors":"Natalie L. Hauglund, Mie Andersen, Klaudia Tokarska, Tessa Radovanovic, Celia Kjaerby, Frederikke L. Sørensen, Zuzanna Bojarowska, Verena Untiet, Sheyla B. Ballestero, Mie G. Kolmos, Pia Weikop, Hajime Hirase, Maiken Nedergaard","doi":"10.1016/j.cell.2024.11.027","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.027","url":null,"abstract":"As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"77 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936056","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}
Pub Date : 2025-01-02DOI: 10.1016/j.cell.2024.11.036
Matthew K. Howard, Nicholas Hoppe, Xi-Ping Huang, Darko Mitrovic, Christian B. Billesbølle, Christian B. Macdonald, Eshan Mehrotra, Patrick Rockefeller Grimes, Donovan D. Trinidad, Lucie Delemotte, Justin G. English, Willow Coyote-Maestas, Aashish Manglik
Three proton-sensing G protein-coupled receptors (GPCRs)—GPR4, GPR65, and GPR68—respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity.
{"title":"Molecular basis of proton sensing by G protein-coupled receptors","authors":"Matthew K. Howard, Nicholas Hoppe, Xi-Ping Huang, Darko Mitrovic, Christian B. Billesbølle, Christian B. Macdonald, Eshan Mehrotra, Patrick Rockefeller Grimes, Donovan D. Trinidad, Lucie Delemotte, Justin G. English, Willow Coyote-Maestas, Aashish Manglik","doi":"10.1016/j.cell.2024.11.036","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.036","url":null,"abstract":"Three proton-sensing G protein-coupled receptors (GPCRs)—GPR4, GPR65, and GPR68—respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"92 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912175","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}
Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of HECL2-45.47 and H7.36 enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular HECL2-45.41 contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.
{"title":"Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4","authors":"Xin Wen, Pan Shang, Haidi Chen, Lulu Guo, Naikang Rong, Xiaoyu Jiang, Xuan Li, Junyan Liu, Gongming Yang, Jiacheng Zhang, Kongkai Zhu, Qingbiao Meng, Xuefei He, Zhihai Wang, Zili Liu, Haoran Cheng, Yilin Zheng, Bifei Zhang, Jiaojiao Pang, Zhaoqian Liu, Jin-Peng Sun","doi":"10.1016/j.cell.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.001","url":null,"abstract":"Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of <em>Xenopus tropicalis</em> GPR4 (xtGPR4) and <em>Mus musculus</em> GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of H<sup>ECL2-45.47</sup> and H<sup>7.36</sup> enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular H<sup>ECL2-45.41</sup> contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"6 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912184","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}
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