bioRxiv : the preprint server for biology最新文献_第6页

Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors. 实体瘤中罕见的强效效应CD8 T细胞的多模式鉴定。

bioRxiv : the preprint server for biology Pub Date : 2025-02-16 DOI: 10.1101/2023.09.26.559470

Arja Ray, Molly Bassette, Kenneth H Hu, Lomax F Pass, Tristan Courau, Bushra Samad, Alexis Combes, Vrinda Johri, Brittany Davidson, Katherine Wai, Patrick Ha, Grace Hernandez, Itzia Zaleta-Linares, Matthew F Krummel

{"title":"Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors.","authors":"Arja Ray, Molly Bassette, Kenneth H Hu, Lomax F Pass, Tristan Courau, Bushra Samad, Alexis Combes, Vrinda Johri, Brittany Davidson, Katherine Wai, Patrick Ha, Grace Hernandez, Itzia Zaleta-Linares, Matthew F Krummel","doi":"10.1101/2023.09.26.559470","DOIUrl":"10.1101/2023.09.26.559470","url":null,"abstract":"The anti-tumor function of CD8 T cells is limited through well-established pathways of T cell exhaustion (T EX ). Strategies to capture emergent functional states amongst this dominant trajectory of dysfunction are necessary to find pathways to durable anti-tumor immunity. By leveraging transcriptional reporting (by the fluorescent protein TFP) of the T cell activation marker Cd69, related to upstream AP-1 transcription factors, we define a classifier for potent versus sub-optimal CD69+ activation states arising from T cell stimulation. In tumors, this delineation acts an additional functional readout along the T EX differentiation trajectory, within and across T EX subsets, marked by enhanced effector cytokine and granzyme B production. The more potent state remains differentially prominent in a T cell-mediated tumor clearance model, where they also show increased engagement in the microenvironment and are superior in tumor cell killing. Employing multimodal CITE-Seq in human head and neck tumors enables a similar strategy to identify Cd69RNA hi CD69+ cells that also have enhanced functional features in comparison to Cd69RNA lo CD69+ cells, again within and across intratumoral CD8 T cell subsets. Refining the contours of the T cell functional landscape in tumors in this way paves the way for the identification of rare exceptional effectors, with imminent relevance to cancer treatment.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/04/1a/nihpp-2023.09.26.559470v1.PMC10557647.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CellSAM: A Foundation Model for Cell Segmentation. 细胞分割的基础模型。

bioRxiv : the preprint server for biology Pub Date : 2025-02-16 DOI: 10.1101/2023.11.17.567630

Uriah Israel, Markus Marks, Rohit Dilip, Qilin Li, Changhua Yu, Emily Laubscher, Ahamed Iqbal, Elora Pradhan, Ada Ates, Martin Abt, Caitlin Brown, Edward Pao, Shenyi Li, Alexander Pearson-Goulart, Pietro Perona, Georgia Gkioxari, Ross Barnowski, Yisong Yue, David Van Valen

{"title":"CellSAM: A Foundation Model for Cell Segmentation.","authors":"Uriah Israel, Markus Marks, Rohit Dilip, Qilin Li, Changhua Yu, Emily Laubscher, Ahamed Iqbal, Elora Pradhan, Ada Ates, Martin Abt, Caitlin Brown, Edward Pao, Shenyi Li, Alexander Pearson-Goulart, Pietro Perona, Georgia Gkioxari, Ross Barnowski, Yisong Yue, David Van Valen","doi":"10.1101/2023.11.17.567630","DOIUrl":"10.1101/2023.11.17.567630","url":null,"abstract":"Cells are a fundamental unit of biological organization, and identifying them in imaging data - cell segmentation - is a critical task for various cellular imaging experiments. While deep learning methods have led to substantial progress on this problem, most models are specialist models that work well for specific domains but cannot be applied across domains or scale well with large amounts of data. In this work, we present CellSAM, a universal model for cell segmentation that generalizes across diverse cellular imaging data. CellSAM builds on top of the Segment Anything Model (SAM) by developing a prompt engineering approach for mask generation. We train an object detector, CellFinder, to automatically detect cells and prompt SAM to generate segmentations. We show that this approach allows a single model to achieve human-level performance for segmenting images of mammalian cells, yeast, and bacteria collected across various imaging modalities. We show that CellSAM has strong zero-shot performance and can be improved with a few examples via few-shot learning. Additionally, we demonstrate how CellSAM can be applied across diverse bioimage analysis workflows. A deployed version of CellSAM is available at https://cellsam.deepcell.org/.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The information bottleneck as a principle underlying multi-area cortical representations during decision-making. 决策过程中的皮层信息瓶颈。

bioRxiv : the preprint server for biology Pub Date : 2025-02-15 DOI: 10.1101/2023.07.12.548742

Michael Kleinman, Tian Wang, Derek Xiao, Ebrahim Feghhi, Kenji Lee, Nicole Carr, Yuke Li, Nima Hadidi, Chandramouli Chandrasekaran, Jonathan C Kao

{"title":"The information bottleneck as a principle underlying multi-area cortical representations during decision-making.","authors":"Michael Kleinman, Tian Wang, Derek Xiao, Ebrahim Feghhi, Kenji Lee, Nicole Carr, Yuke Li, Nima Hadidi, Chandramouli Chandrasekaran, Jonathan C Kao","doi":"10.1101/2023.07.12.548742","DOIUrl":"10.1101/2023.07.12.548742","url":null,"abstract":"Decision-making emerges from distributed computations across multiple brain areas, but it is unclear why the brain distributes the computation. In deep learning, artificial neural networks use multiple areas (or layers) and form optimal representations of task inputs. These optimal representations are sufficient to perform the task well, but minimal so they are invariant to other irrelevant variables. We recorded single neurons and multiunits in dorsolateral prefrontal cortex (DLPFC) and dorsal premotor cortex (PMd) in monkeys during a perceptual decision-making task. We found that while DLPFC represents task-related inputs required to compute the choice, the downstream PMd contains a minimal sufficient, or optimal, representation of the choice. To identify a mechanism for how cortex may form these optimal representations, we trained a multi-area recurrent neural network (RNN) to perform the task. Remarkably, DLPFC and PMd resembling representations emerged in the early and late areas of the multi-area RNN, respectively. The DLPFC-resembling area partially orthogonalized choice information and task inputs and this choice information was preferentially propagated to downstream areas through selective alignment with inter-area connections, while remaining task information was not. Our results suggest that cortex uses multi-area computation to form minimal sufficient representations by preferential propagation of relevant information between areas.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10369960/pdf/nihpp-2023.07.12.548742v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9884104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Changes of cell-type diversity in the polyp-to-medusa metagenesis of the scyphozoan jellyfish Aurelia coerulea (formerly sp.1). 一份来自棘纲水母的细胞类型图谱提供了从珊瑚虫到水母转变过程中细胞类型多样性变化的见解

bioRxiv : the preprint server for biology Pub Date : 2025-02-15 DOI: 10.1101/2023.08.24.554571

Oliver Link, Stefan M Jahnel, Kristin Janicek, Johanna Kraus, Juan Daniel Montenegro, Bob Zimmerman, Brittney Wick, Alison G Cole, Ulrich Technau

{"title":"Changes of cell-type diversity in the polyp-to-medusa metagenesis of the scyphozoan jellyfish Aurelia coerulea (formerly sp.1).","authors":"Oliver Link, Stefan M Jahnel, Kristin Janicek, Johanna Kraus, Juan Daniel Montenegro, Bob Zimmerman, Brittney Wick, Alison G Cole, Ulrich Technau","doi":"10.1101/2023.08.24.554571","DOIUrl":"10.1101/2023.08.24.554571","url":null,"abstract":"The life cycle of most medusozoan cnidarians is marked by the metagenesis from the asexually reproducing sessile polyp and the sexually reproducing motile medusa. At present it is unknown to what extent this drastic morphological transformation is accompanied by changes in the cell type composition. Here, we provide a single cell transcriptome atlas of the cosmopolitan scyphozoan Aurelia coerulea focussing on changes in cell-type composition during the transition from polyp to medusa. Notably, this transition marked by an increase in cell type diversity, including an expansion of neural subtypes. We find that two families of neuronal lineages are specified by homologous transcription factors in the sea anemone Nematostella vectensis and Aurelia coerulea, suggesting an origin in the common ancestor of medusozoans and anthozoans about 500 Myr ago. Our analysis suggests that gene duplications might be drivers for the increase of cellular complexity during the evolution of cnidarian neuroglandular lineages. One key medusozoan-specific cell type is the striated muscle in the subumbrella. Analysis of muscle fiber anatomy and gene expression raises the possibility that the striated muscles arise from a population of smooth muscle cells during strobilation. Although smooth and striated muscles are phenotypically distinct, both have a similar contractile complex, in contrast to bilaterian smooth and striated muscles. This suggests that in Aurelia, smooth and striated muscle cells may derive from the same progenitor cells.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84405827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disruption of Synaptic Endoplasmic Reticulum Luminal Protein Containment in Drosophila Atlastin Mutants. Atlastin突变体突触前ER网络的高分辨率成像。

bioRxiv : the preprint server for biology Pub Date : 2025-02-15 DOI: 10.1101/2023.09.01.555994

Mónica C Quiñones-Frías, Dina M Ocken, Avital Rodal

{"title":"Disruption of Synaptic Endoplasmic Reticulum Luminal Protein Containment in Drosophila Atlastin Mutants.","authors":"Mónica C Quiñones-Frías, Dina M Ocken, Avital Rodal","doi":"10.1101/2023.09.01.555994","DOIUrl":"10.1101/2023.09.01.555994","url":null,"abstract":"The endoplasmic reticulum (ER) extends throughout neurons and regulates many neuronal functions, including neurite outgrowth, neurotransmission, and synaptic plasticity. Mutations in proteins that control ER shape are linked to the neurodegenerative disorder Hereditary Spastic Paraplegia (HSP), yet the ultrastructure and dynamics of neuronal ER remain largely unexplored, especially at presynaptic terminals. Using super-resolution and live imaging in D. melanogaster larval motor neurons, we investigated ER structure at presynaptic terminals of wild-type animals and null mutants of the ER shaping protein and HSP-linked gene, Atlastin. Previous studies using an ER luminal marker reported diffuse localization at Atlastin mutant presynaptic terminals, which was attributed to ER fragmentation. However, using an ER membrane marker, we discovered that Atlastin mutant ER forms robust networks with only mild defects in structural dynamics, indicating the primary defect is functional rather than architectural. We demonstrate that Atlastin mutants progressively displace overexpressed luminal ER proteins to the cytosol during larval development, specifically at synapses, while these proteins remain correctly localized in cell bodies, axons, and muscles. This synaptic-specific displacement phenotype, previously unreported in non-neuronal cells, emphasizes the importance of studying neurons to understand HSP pathogenesis.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c6/5c/nihpp-2023.09.01.555994v1.PMC10491308.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10263491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Barcode-free multiplex plasmid sequencing using Bayesian analysis and nanopore sequencing. 使用贝叶斯分析和纳米孔测序的无条形码多重质粒测序。

bioRxiv : the preprint server for biology Pub Date : 2025-02-13 DOI: 10.1101/2023.04.12.536413

Masaaki Uematsu, Jeremy M Baskin

{"title":"Barcode-free multiplex plasmid sequencing using Bayesian analysis and nanopore sequencing.","authors":"Masaaki Uematsu, Jeremy M Baskin","doi":"10.1101/2023.04.12.536413","DOIUrl":"10.1101/2023.04.12.536413","url":null,"abstract":"Plasmid construction is central to life science research, and sequence verification is arguably its costliest step. Long-read sequencing has emerged as a competitor to Sanger sequencing, with the principal benefit that whole plasmids can be sequenced in a single run. Nevertheless, the current cost of nanopore sequencing is still prohibitive for routine sequencing during plasmid construction. We develop a computational approach termed Simple Algorithm for Very Efficient Multiplexing of Oxford Nanopore Experiments for You (SAVEMONEY) that guides researchers to mix multiple plasmids and subsequently computationally de-mixes the resultant sequences. SAVEMONEY defines optimal mixtures in a pre-survey step, and following sequencing, executes a post-analysis workflow involving sequence classification, alignment, and consensus determination. By using Bayesian analysis with prior probability of expected plasmid construction error rate, high-confidence sequences can be obtained for each plasmid in the mixture. Plasmids differing by as little as two bases can be mixed for submission as a single sample for nanopore sequencing, and routine multiplexing of even six plasmids per 180 reads can still maintain high accuracy of consensus sequencing. SAVEMONEY should further democratize whole-plasmid sequencing by nanopore and related technologies, driving down the effective cost of whole-plasmid sequencing to lower than that of a single Sanger sequencing run.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/14/e4/nihpp-2023.04.12.536413v2.PMC10120676.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9391431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Normative evidence weighing and accumulation in correlated environments. 相关环境中的规范证据加权和积累。

bioRxiv : the preprint server for biology Pub Date : 2025-02-08 DOI: 10.1101/2024.05.29.596489

Nathan Tardiff, Jiwon Kang, Joshua I Gold

引用次数: 0

Social context and the evolution of delayed reproduction in birds. 社会环境和鸟类延迟繁殖的进化。

bioRxiv : the preprint server for biology Pub Date : 2025-02-07 DOI: 10.1101/2023.08.02.551693

Liam U Taylor, Josef C Uyeda, Richard O Prum

{"title":"Social context and the evolution of delayed reproduction in birds.","authors":"Liam U Taylor, Josef C Uyeda, Richard O Prum","doi":"10.1101/2023.08.02.551693","DOIUrl":"10.1101/2023.08.02.551693","url":null,"abstract":"One puzzling feature of avian life histories is that individuals in many different lineages delay reproduction for several years after they finish growing. Intraspecific field studies suggest that various complex social contexts-such as cooperative breeding groups, nesting colonies, and display leks-result in delayed reproduction because they require forms of sociosexual development that extend beyond physical maturation. Here, we explicitly propose this hypothesis and use a full suite of phylogenetic comparative methods to test it, analyzing the evolution of age at first reproduction (AFR) in females and males across 963 species of birds. Phylogenetic regressions support increased AFR in colonial females and males, cooperatively breeding males, and lekking males. Continuous Ornstein-Uhlenbeck models support distinct evolutionary regimes with increased AFR for all of cooperative, colonial, and lekking lineages. Discrete hidden state Markov models suggest a net increase in delayed reproduction for social lineages, even when accounting for hidden state heterogeneity and the potential reverse influence of AFR on sociality. Our results support the hypothesis that the evolution of social contexts reshapes the dynamics of life history evolution in birds. Comparative analyses of even the most broadly generalizable characters, such as AFR, must reckon with unique, heterogeneous, historical events in the evolution of individual lineages.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cb/cd/nihpp-2023.08.02.551693v1.PMC10418290.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10038219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigating tumor-associated macrophages and their polarization in colorectal cancer using Boolean implication networks. 大肠癌中肿瘤相关巨噬细胞及其极化的人工智能辅助研究

bioRxiv : the preprint server for biology Pub Date : 2025-02-06 DOI: 10.1101/2023.08.01.551559

Ekta Dadlani, Tirtharaj Dash, Debashis Sahoo

{"title":"Investigating tumor-associated macrophages and their polarization in colorectal cancer using Boolean implication networks.","authors":"Ekta Dadlani, Tirtharaj Dash, Debashis Sahoo","doi":"10.1101/2023.08.01.551559","DOIUrl":"10.1101/2023.08.01.551559","url":null,"abstract":"Tumor-associated Macrophages (or TAMs) are amongst the most common cells that play a significant role in the initiation and progression of colorectal cancer (CRC). [Ghosh et al., 2023] have built a Boolean-logic dependent model to propose a set of gene signatures capable of identifying macrophage polarization states. The signature, called the Signature of Macrophage Reactivity and Tolerance (SMaRT), comprises of 338 human genes (equivalently, 298 mouse genes). The SMaRT signature was constructed using datasets that were not specialized towards any particular disease. To specifically investigate macrophage polarization in CRC, in this paper, we (a) perform a comprehensive analysis of the SMaRT signature on single-cell human and mouse colorectal cancer RNA-seq datasets and (b) adopt transfer learning to construct a \"refined\" SMaRT signature that specifically characterizes TAM polarization in the CRC tumor microenvironment. Towards validation of our refined gene signature, we use: (a) 5 RNA-seq datasets derived from single-cell human datasets; and (b) 5 large-cohort microarray datasets from humans. Furthermore, we propose the translational potential of our refined gene signature while investigating microsatellite stability and CpG island methylator phenotype (CIMP) in colorectal cancer. Overall, our refined gene signature and its extensive validation provide a path for its adoption in clinical practice in diagnosing colorectal cancer and associated attributes.Availability and implementation: The data, codes, and software packages used in our research are linked and shared publicly at https://github.com/tirtharajdash/TAMs-CRC .","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9993255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct Activation Mechanisms of CXCR4 and ACKR3 Revealed by Single-Molecule Analysis of their Conformational Landscapes. 通过对CXCR4和ACKR3构象的单分子分析揭示其不同的激活机制。

bioRxiv : the preprint server for biology Pub Date : 2025-02-06 DOI: 10.1101/2023.10.31.564925

Christopher T Schafer, Raymond F Pauszek, Martin Gustavsson, Tracy M Handel, David P Millar

{"title":"Distinct Activation Mechanisms of CXCR4 and ACKR3 Revealed by Single-Molecule Analysis of their Conformational Landscapes.","authors":"Christopher T Schafer, Raymond F Pauszek, Martin Gustavsson, Tracy M Handel, David P Millar","doi":"10.1101/2023.10.31.564925","DOIUrl":"10.1101/2023.10.31.564925","url":null,"abstract":"The canonical chemokine receptor CXCR4 and atypical receptor ACKR3 both respond to CXCL12 but induce different effector responses to regulate cell migration. While CXCR4 couples to G proteins and directly promotes cell migration, ACKR3 is G protein-independent and scavenges CXCL12 to regulate extracellular chemokine levels and maintain CXCR4 responsiveness, thereby indirectly influencing migration. The receptors also have distinct activation requirements. CXCR4 only responds to wild-type CXCL12 and is sensitive to mutation of the chemokine. By contrast, ACKR3 recruits GPCR kinases (GRKs) and β-arrestins and promiscuously responds to CXCL12, CXCL12 variants, other peptides and proteins, and is relatively insensitive to mutation. To investigate the role of conformational dynamics in the distinct pharmacological behaviors of CXCR4 and ACKR3, we employed single-molecule FRET to track discrete conformational states of the receptors in real-time. The data revealed that apo-CXCR4 preferentially populates a high-FRET inactive state, while apo-ACKR3 shows little conformational preference and high transition probabilities among multiple inactive, intermediate and active conformations, consistent with its propensity for activation. Multiple active-like ACKR3 conformations are populated in response to agonists, compared to the single CXCR4 active-state. This and the markedly different conformational landscapes of the receptors suggest that activation of ACKR3 may be achieved by a broader distribution of conformational states than CXCR4. Much of the conformational heterogeneity of ACKR3 is linked to a single residue that differs between ACKR3 and CXCR4. The dynamic properties of ACKR3 may underly its inability to form productive interactions with G proteins that would drive canonical GPCR signaling.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0