Journal of Molecular Biology最新文献_第3页

Phospholipid Transport Across the Bacterial Periplasm Through the Envelope-spanning Bridge YhdP.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-12-06 DOI: 10.1016/j.jmb.2024.168891

Benjamin F Cooper, Robert Clark, Anju Kudhail, Dali Dunn, Qiaoyu Tian, Gira Bhabha, Damian C Ekiert, Syma Khalid, Georgia L Isom

{"title":"Phospholipid Transport Across the Bacterial Periplasm Through the Envelope-spanning Bridge YhdP.","authors":"Benjamin F Cooper, Robert Clark, Anju Kudhail, Dali Dunn, Qiaoyu Tian, Gira Bhabha, Damian C Ekiert, Syma Khalid, Georgia L Isom","doi":"10.1016/j.jmb.2024.168891","DOIUrl":"10.1016/j.jmb.2024.168891","url":null,"abstract":"The outer membrane of Gram-negative bacteria provides a formidable barrier, essential for both pathogenesis and antimicrobial resistance. Biogenesis of this complex structure necessitates the transport of phospholipids across the cell envelope. Recently, YhdP was implicated as a major protagonist in the trafficking of inner membrane phospholipids to the outer membrane; however the molecular mechanism of YhdP mediated transport remains elusive. Here, utilising AlphaFold, we observe YhdP to form an elongated assembly of 60 β-strands that curve to form a continuous hydrophobic groove. This architecture is consistent with our negative stain electron microscopy data which reveals YhdP to be approximately 250 Å in length and thus sufficient to span the bacterial cell envelope. Furthermore, molecular dynamics simulations and bacterial growth assays indicate essential helical regions at the N- and C-termini of YhdP, that may embed into the inner and outer membranes respectively, reinforcing its envelope spanning nature. Our in vivo crosslinking data reveal phosphate-containing substrates captured along the length of the YhdP groove, providing direct evidence that YhdP interacts with a phosphate-containing substrate, which we propose to be phospholipids. This finding is congruent with our molecular dynamics simulations which demonstrate the propensity for inner membrane lipids to spontaneously enter the groove of YhdP. Collectively, our results support a model in which YhdP bridges the cell envelope, providing a hydrophobic environment for the transport of phospholipids to the outer membrane.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168891"},"PeriodicalIF":4.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Gradations in protein dynamics captured by experimental NMR are not well represented by AlphaFold2 models and other computational metrics.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-12-06 DOI: 10.1016/j.jmb.2024.168900

Jose Gavalda-Garcia, Bhawna Dixit, Adrián Díaz, An Ghysels, Wim Vranken

{"title":"Gradations in protein dynamics captured by experimental NMR are not well represented by AlphaFold2 models and other computational metrics.","authors":"Jose Gavalda-Garcia, Bhawna Dixit, Adrián Díaz, An Ghysels, Wim Vranken","doi":"10.1016/j.jmb.2024.168900","DOIUrl":"10.1016/j.jmb.2024.168900","url":null,"abstract":"The advent of accurate methods to predict the fold of proteins initiated by AlphaFold2 is rapidly changing our understanding of proteins and helping their design. However, these methods are mainly trained on protein structures determined with X-ray diffraction, where the protein is packed in crystals at often cryogenic temperatures. They can therefore only reliably cover well-folded parts of proteins that experience few, if any, conformational changes. Experimentally, solution nuclear magnetic resonance (NMR) is the experimental method of choice to gain insight into protein dynamics at near physiological conditions. Computationally, methods such as molecular dynamics (MD) simulations and Normal Mode Analysis (NMA) allow the estimation of a protein's intrinsic flexibility based on a single protein structure. This work addresses, on a large scale, the relationships for proteins between the AlphaFold2 pLDDT metric, the observed dynamics in solution from NMR metrics, interpreted MD simulations, and the computed dynamics with NMA from single AlphaFold2 models and NMR ensembles. We observe that these metrics agree well for rigid residues that adopt a single well-defined conformation, which are clearly distinct from residues that exhibit dynamic behavior and adopt multiple conformations. This direct order/disorder categorisation is reflected in the correlations observed between the parameters, but becomes very limited when considering only the likely dynamic residues. The gradations of dynamics observed by NMR in flexible protein regions are therefore not represented by these computational approaches. Our results are interactively available for each protein from https://bio2byte.be/af_nmr_nma/.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168900"},"PeriodicalIF":4.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Rabies Virus Phosphoprotein Exhibits Thermoresponsive Phase Separation with a Lower Critical Solution Temperature.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-12-05 DOI: 10.1016/j.jmb.2024.168889

Fella Bouchama, Khadeeja Mubashira, Caroline Mas, Aline Le Roy, Christine Ebel, Jean-Marie Bourhis, Thomas Zemb, Sylvain Prevost, Marc Jamin

{"title":"Rabies Virus Phosphoprotein Exhibits Thermoresponsive Phase Separation with a Lower Critical Solution Temperature.","authors":"Fella Bouchama, Khadeeja Mubashira, Caroline Mas, Aline Le Roy, Christine Ebel, Jean-Marie Bourhis, Thomas Zemb, Sylvain Prevost, Marc Jamin","doi":"10.1016/j.jmb.2024.168889","DOIUrl":"10.1016/j.jmb.2024.168889","url":null,"abstract":"Rabies virus (RABV) generates membrane-less liquid organelles (Negri bodies) in the cytoplasm of its host cell, where genome transcription and replication and nucleocapsid assembly take place, but the mechanisms of their assembly and maturation remain to be explained. An essential component of the viral RNA synthesizing machine, the phosphoprotein (P), acts as a scaffold protein for the assembly of these condensates. This intrinsically disordered protein forms star-shaped dimers with N-terminal negatively charged flexible arms and C-terminal globular domains exhibiting a large dipole moment. Our study shows that in vitro self-association of RABV P drives a complex thermoresponsive phase separation with a lower critical solution temperature. Protein dimers assemble already below the saturation concentration, and condensation is driven by attractive conformation-specific interactions leading to reentrant liquid phase separation over a narrow range of salt concentration. We propose a minimal molecular model in which P can adopt three limit conformational states and the disordered N-terminal arms control the interactions between giant dipoles that is consistent with our observations.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168889"},"PeriodicalIF":4.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Integrated Multi-Omics Analyses Reveal Lipid Metabolic Signature in Osteoarthritis.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-12-04 DOI: 10.1016/j.jmb.2024.168888

Yang Wang, Tianyu Zeng, Deqin Tang, Haipeng Cui, Ying Wan, Hua Tang

{"title":"Integrated Multi-Omics Analyses Reveal Lipid Metabolic Signature in Osteoarthritis.","authors":"Yang Wang, Tianyu Zeng, Deqin Tang, Haipeng Cui, Ying Wan, Hua Tang","doi":"10.1016/j.jmb.2024.168888","DOIUrl":"10.1016/j.jmb.2024.168888","url":null,"abstract":"Osteoarthritis (OA) is the most common degenerative joint disease and the second leading cause of disability worldwide. Single-omics analyses are far from elucidating the complex mechanisms of lipid metabolic dysfunction in OA. This study identified a shared lipid metabolic signature of OA by integrating metabolomics, single-cell and bulk RNA-seq, as well as metagenomics. Compared to the normal counterparts, cartilagesin OA patients exhibited significant depletion of homeostatic chondrocytes (HomCs) (P = 0.03) and showed lipid metabolic disorders in linoleic acid metabolism and glycerophospholipid metabolism which was consistent with our findings obtained from plasma metabolomics. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), weidentified PLA2G2A as a hub gene associated with lipid metabolic disorders in HomCs. And an OA-associated subtype of HomCs, namely HomC1 (marked by PLA2G2A, MT-CO1, MT-CO2, and MT-CO3) was identified, which also exhibited abnormal activation of lipid metabolic pathways. This suggests the involvement of HomC1 in OA progression through the shared lipid metabolism aberrancies, which were further validated via bulk RNA-Seq analysis. Metagenomic profiling identified specific gut microbial species significantly associated with the key lipid metabolism disorders, including Bacteroides uniformis (P < 0.001, R = -0.52), Klebsiella pneumonia (P = 0.003, R = 0.42), Intestinibacter_bartlettii (P = 0.009, R = 0.38), and Streptococcus anginosus (P = 0.009, R = 0.38). By integrating the multi-omics features, a random forest diagnostic model with outstanding performance was developed (AUC = 0.97). In summary, this study deciphered the crucial role of a integrated lipid metabolic signature in OA pathogenesis, and established a regulatory axis of gut microbiota-metabolites-cell-gene, providing new insights into the gut-joint axis and precision therapy for OA.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168888"},"PeriodicalIF":4.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

TCM-ADIP: A Multidimensional Database Linking Traditional Chinese Medicine to Functional Brain Zones of Alzheimer's Disease. TCM-ADIP：连接传统中医药与阿尔茨海默病脑功能区的多维数据库。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-12-03 DOI: 10.1016/j.jmb.2024.168874

Lianjiang Hu, Qiang Tang, Fanbo Meng, Yixi Xu, Wei Chen, Shijun Xu

{"title":"TCM-ADIP: A Multidimensional Database Linking Traditional Chinese Medicine to Functional Brain Zones of Alzheimer's Disease.","authors":"Lianjiang Hu, Qiang Tang, Fanbo Meng, Yixi Xu, Wei Chen, Shijun Xu","doi":"10.1016/j.jmb.2024.168874","DOIUrl":"10.1016/j.jmb.2024.168874","url":null,"abstract":"Alzheimer's disease (AD) is a complex neurodegenerative disorder, with existing therapeutic drugs typically targeting specific disease stages. Traditional Chinese medicine (TCM), known for its multi-target and multi-mechanism therapeutic approach, has demonstrated efficacy in treating various stages of AD. In the present work, through a systematic review of classical Chinese medical texts, the formulae for preventing and treating AD were identified. Meanwhile, the active ingredients within these formulae were extracted and cataloged. A comprehensive bioinformatics analysis of omics data was performed to identify differentially expressed genes across different functional brain zones in AD patients at various stages. Finally, by integrating the multidimensional data, we proposed the first database, TCM-ADIP, dedicated to TCM based AD prevention and treatment, which is freely available at https://cbcb.cdutcm.edu.cn/TCM-ADIP/. TCM-ADIP not only supports interactive searching of multidimensional data, but also provides tools for gene localization and functional enrichment analysis of formulae, herbs, and ingredients for AD intervention in specific brain zones. TCM-ADIP fills a crucial gap in existing databases, offering a comprehensive resource for TCM in the treatment of AD.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168874"},"PeriodicalIF":4.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exploring Regulatory Roles of Transposable Elements in EMT and MET through Data-Driven Analysis: Insights from regulaTER.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-12-02 DOI: 10.1016/j.jmb.2024.168887

Doğa Eskier, Seray Yetkin, Nazmiye Arslan, Gökhan Karakülah, Hani Alotaibi

{"title":"Exploring Regulatory Roles of Transposable Elements in EMT and MET through Data-Driven Analysis: Insights from regulaTER.","authors":"Doğa Eskier, Seray Yetkin, Nazmiye Arslan, Gökhan Karakülah, Hani Alotaibi","doi":"10.1016/j.jmb.2024.168887","DOIUrl":"10.1016/j.jmb.2024.168887","url":null,"abstract":"Gene expression is regulated at the transcriptional and translational levels and a plethora of epigenetic mechanisms. Regulation of gene expression by transposable elements is well documented. However, a comprehensive analysis of their regulatory roles is challenging due to the lack of dedicated approaches to define their contribution. Here, we present regulaTER, a new R library dedicated to deciphering the regulatory potential of transposable elements in a given phenotype. regulaTER utilizes a variety of genomics data of any origin and combines gene expression level information to predict the regulatory roles of transposable elements. We further validated its capabilities using data generated from an epithelial-mesenchymal and mesenchymal-epithelial transition cellular model. regulaTER stands out as an essential asset for uncovering the impact of transposable elements on the regulation of gene expression, with high flexibility to perform a range of transposable element-focused analyses. Our results also provided insights on the contribution of the MIR and B element subfamilies in regulating EMT and MET through the FoxA transcription factor family. regulaTER is publicly available and can be downloaded from https://github.com/karakulahg/regulaTER.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168887"},"PeriodicalIF":4.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Intrinsically Disordered RNA Binding Protein Modulates mRNA Translation and Storage.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-11-29 DOI: 10.1016/j.jmb.2024.168884

Xin Chen, Mashiat N Chowdhury, Hong Jin

{"title":"An Intrinsically Disordered RNA Binding Protein Modulates mRNA Translation and Storage.","authors":"Xin Chen, Mashiat N Chowdhury, Hong Jin","doi":"10.1016/j.jmb.2024.168884","DOIUrl":"10.1016/j.jmb.2024.168884","url":null,"abstract":"Proteins with intrinsically disordered regions (IDR) play diverse functions in regulating gene expression in the cell. Many of these proteins interact with cytoplasmic ribosomes. However, the molecular functions related to the interactions are largely unclear. In this study, using an abundant RNA-binding protein, Sbp1, with a structurally well-defined RNA recognition motif and an intrinsically disordered RGG domain as a model system, we investigated how an RNA binding protein with IDR modulates mRNA storage and translation. Using genomic and molecular approaches, we show that Sbp1 slows ribosome movement on cellular mRNAs and promotes polysome stacking or aggregation. Sbp1-associated polysomes display a ring-shaped structure in addition to a beads-on-string morphology visualized under the electron microscope, likely to be an intermediate slow translation state between actively translating polysomes and the translation-sequestered RNA granule. Moreover, the binding of Sbp1 to the 5'UTRs of mRNAs represses both cap-dependent and cap-independent translation initiation of proteins, many are functionally important for general protein synthesis in the cell. Finally, post-translational modifications at the arginine in the RGG motif change the Sbp1 protein interactome and play important roles in directing cellular mRNAs to either translation or storage. Taken together, our study demonstrates that under physiological conditions, intrinsically disordered RNA binding proteins promote polysome aggregation and regulate mRNA translation and storage using multiple distinctive mechanisms. This research also establishes a framework with which functions of other IDR-containing proteins can be investigated and defined.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168884"},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Human B-cells can form Hetero-aggregates with Blood Platelets: A Novel Insight into Adaptive Immunity Regulation in Multiple Sclerosis.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-11-28 DOI: 10.1016/j.jmb.2024.168885

Karina Maciak, Angela Dziedzic, Jacek Szymański, Maciej Studzian, Justyna Redlicka, Elżbieta Miller, Sylwia Michlewska, Piotr Jóźwiak, Joanna Saluk

{"title":"Human B-cells can form Hetero-aggregates with Blood Platelets: A Novel Insight into Adaptive Immunity Regulation in Multiple Sclerosis.","authors":"Karina Maciak, Angela Dziedzic, Jacek Szymański, Maciej Studzian, Justyna Redlicka, Elżbieta Miller, Sylwia Michlewska, Piotr Jóźwiak, Joanna Saluk","doi":"10.1016/j.jmb.2024.168885","DOIUrl":"10.1016/j.jmb.2024.168885","url":null,"abstract":"Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and neurodegeneration. Our original study analyzes the interactions between blood platelets and leukocytes in MS, focused on their potential role in modulating immune responses. We demonstrated, for the first time, a significant increase in leukocyte migration towards platelets, indicating their higher chemotactic capabilities in MS. This novel finding is supported by microscopic imaging of platelet-leukocyte hetero-aggregates (PLAs). Our study included platelet activation status and platelet-lymphocyte cross-talk analysis distinguishing lymphocytic subpopulation in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS) compared to healthy controls (HC). Flow cytometry method revealed an elevated expression of platelet activation typical markers i.e. PAC-1 and CD62P in both phenotypes of MS, especially in RRMS, and higher GPVI level in SPMS. Detailed immunophenotyping and confocal imaging showed an increased pool of platelet-lymphocyte aggregates (PLAs-Ly), particularly involving B-cells over T-cells across both MS phenotypes. The study also explored the involvement of the CD40-CD40L pathway, discovering significant correlations between platelet CD40L expression and lymphocytic antigen CD40, especially on B-cells in SPMS. This novel finding may indicate the special significance of platelet-B-cell cross-talk in progressive disease phenotype. Our research identified potential platelet-leukocyte interaction pathways that may influence the lymphocyte-mediated immune response in MS, highlighting the unexplored formation of platelet-B cell hetero-aggregates (PLAs-LyB).","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168885"},"PeriodicalIF":4.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

DciA, the Bacterial Replicative Helicase Loader, Promotes LLPS in the Presence of ssDNA. 细菌复制螺旋酶装载器 DciA 可在 ssDNA 存在的情况下促进 LLPS。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-11-26 DOI: 10.1016/j.jmb.2024.168873

Stéphanie Marsin, Sylvain Jeannin, Sonia Baconnais, Hélène Walbott, Gérard Pehau-Arnaudet, Magali Noiray, Magali Aumont-Nicaise, Emil G P Stender, Claire Cargemel, Romain Le Bars, Eric Le Cam, Sophie Quevillon-Cheruel

{"title":"DciA, the Bacterial Replicative Helicase Loader, Promotes LLPS in the Presence of ssDNA.","authors":"Stéphanie Marsin, Sylvain Jeannin, Sonia Baconnais, Hélène Walbott, Gérard Pehau-Arnaudet, Magali Noiray, Magali Aumont-Nicaise, Emil G P Stender, Claire Cargemel, Romain Le Bars, Eric Le Cam, Sophie Quevillon-Cheruel","doi":"10.1016/j.jmb.2024.168873","DOIUrl":"10.1016/j.jmb.2024.168873","url":null,"abstract":"The loading of the bacterial replicative helicase DnaB is an essential step for genome replication and depends on the assistance of accessory proteins. Several of these proteins have been identified across the bacterial phyla. DciA is the most common loading protein in bacteria, yet the one whose mechanism is the least understood. We have previously shown that DciA from Vibrio cholerae is composed of a globular domain followed by an unfolded extension and demonstrated its strong affinity for DNA. Here, we characterize the condensates formed by VcDciA upon interaction with a short single-stranded DNA substrate. We demonstrate the fluidity of these condensates using light microscopy and address their network organization through electron microscopy, thereby bridging events to conclude on a liquid-liquid phase separation behavior. Additionally, we observe the recruitment of DnaB in the droplets, concomitant with the release of DciA. We show that the well-known helicase loader DnaC from Escherichia coli is also competent to form these phase-separated condensates in the presence of ssDNA. Our phenomenological data are still preliminary as regards the existence of these condensates in vivo, but open the way for exploring the potential involvement of DciA in the formation of non-membrane compartments within the bacterium to facilitate the assembly of replication players on chromosomal DNA.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168873"},"PeriodicalIF":4.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-11-26 DOI: 10.1016/j.jmb.2024.168883

David Sedlak, Roman Tuma, Jayaprakash Narayana Kolla, Raveendra Babu Mokhamatam, Liliia Bahrova, Michaela Lisova, Lenka Bittova, Marek Jindra

{"title":"Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR.","authors":"David Sedlak, Roman Tuma, Jayaprakash Narayana Kolla, Raveendra Babu Mokhamatam, Liliia Bahrova, Michaela Lisova, Lenka Bittova, Marek Jindra","doi":"10.1016/j.jmb.2024.168883","DOIUrl":"10.1016/j.jmb.2024.168883","url":null,"abstract":"Transcription factors of the bHLH-PAS family play vital roles in animal development, physiology, and disease. Two members of the family require binding of low-molecular weight ligands for their activity: the vertebrate aryl hydrocarbon receptor (AHR) and the insect juvenile hormone receptor (JHR). In the fly Drosophila melanogaster, the paralogous proteins GCE and MET constitute the ligand-binding component of JHR complexes. Whilst GCE/MET and AHR are phylogenetically heterologous, their mode of action is similar. JHR is targeted by several synthetic agonists that serve as insecticides disrupting the insect endocrine system. AHR is an important regulator of human endocrine homeostasis, and it responds to environmental pollutants and endocrine disruptors. Whether AHR signaling is affected by compounds that can activate JHR has not been reported. To address this question, we screened a chemical library of 50,000 compounds to identify 93 novel JHR agonists in a reporter system based on Drosophila cells. Of these compounds, 26% modulated AHR signaling in an analogous reporter assay in a human cell line, indicating a significant overlap in the agonist repertoires of the two receptors. To explore the structural features of agonist-dependent activation of JHR and AHR, we compared the ligand-binding cavities and their interactions with selective and common ligands of AHR and GCE. Molecular dynamics modeling revealed ligand-specific as well as conserved side chains within the respective cavities. Significance of predicted interactions was supported through site-directed mutagenesis. The results have indicated that synthetic insect juvenile hormone agonists might interfere with AHR signaling in human cells.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"168883"},"PeriodicalIF":4.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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