Journal of Molecular Biology最新文献_第5页

Mammalian Queuosine tRNA Modification Impacts Translation to Enhance Cell Proliferation and MHC-II Expression. 哺乳动物队列蛋白tRNA修饰通过影响翻译促进细胞增殖和MHC-II表达。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-06 DOI: 10.1016/j.jmb.2025.169188

Olivia N P Zbihley, Katherine Johnson, Luke R Frietze, Wen Zhang, Marcus Foo, Hoang Anh V Tran, Nicolas Chevrier, Tao Pan

{"title":"Mammalian Queuosine tRNA Modification Impacts Translation to Enhance Cell Proliferation and MHC-II Expression.","authors":"Olivia N P Zbihley, Katherine Johnson, Luke R Frietze, Wen Zhang, Marcus Foo, Hoang Anh V Tran, Nicolas Chevrier, Tao Pan","doi":"10.1016/j.jmb.2025.169188","DOIUrl":"10.1016/j.jmb.2025.169188","url":null,"abstract":"<p><p>Queuosine (Q) is a conserved tRNA modification in the wobble anticodon position of tRNAs that read codons of Tyr/His/Asn/Asp. Eukaryotic tRNA Q-modification requires the metabolite queuine - derived from diet or catabolism of the gut microbiome - and a host-genome encoded enzyme complex, QTRT1/QTRT2. tRNA Q-modification has been shown to regulate translational efficiency, but the response of the mammalian transcriptome and tRNAome to tRNA Q-modification in the context of cell proliferation has not been thoroughly investigated. Using cells that differ only in their tRNA Q-modification levels, we found that both human HEK293T cultures and the primary, murine bone marrow-derived dendritic cells (BMDCs) proliferate faster when tRNA Q-modification level is high. We carried out tRNA-seq and mRNA-seq to elucidate the molecular mechanisms underlying this phenotype, revealing distinct tRNA modification and transcriptome changes associated with altered proliferation. In both cell types, the m<sup>2</sup><sub>2</sub>G tRNA modification is positively correlated to Q-modification, consistent with its reported role in enhancing translational efficiency. We also find that elevated Q-modification levels result in transcriptome changes, but in a context-dependent manner. In HEK293T cells, upregulated genes are in catabolic processes and signaling pathway activation; whereas in BMDCs, upregulated genes are in immune response mediation, proliferation, and immunoglobulin diversification. Codon usage analysis of differentially expressed transcripts is consistent with Q-modification enhancing the translation of ribosomal proteins, which increases cell proliferation. We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169188"},"PeriodicalIF":4.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955969","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 acetylated Lysine Residue of Its Low-glucose Inhibitory Domain Controls Activity and Protein Interactions of ChREBP 其低糖抑制区域的乙酰化赖氨酸残基控制ChREBP的活性和蛋白质相互作用。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-06 DOI: 10.1016/j.jmb.2025.169189

Konstantin M. Petricek , Marieluise Kirchner , Manuela Sommerfeld , Heike Stephanowitz , Marie F. Kiefer , Yueming Meng , Sarah Dittrich , Henriette E. Dähnhardt , Knut Mai , Eberhard Krause , Philipp Mertins , Sylvia J. Wowro , Michael Schupp

{"title":"An acetylated Lysine Residue of Its Low-glucose Inhibitory Domain Controls Activity and Protein Interactions of ChREBP","authors":"Konstantin M. Petricek , Marieluise Kirchner , Manuela Sommerfeld , Heike Stephanowitz , Marie F. Kiefer , Yueming Meng , Sarah Dittrich , Henriette E. Dähnhardt , Knut Mai , Eberhard Krause , Philipp Mertins , Sylvia J. Wowro , Michael Schupp","doi":"10.1016/j.jmb.2025.169189","DOIUrl":"10.1016/j.jmb.2025.169189","url":null,"abstract":"<div><div>Carbohydrate response element-binding protein (ChREBP) is a transcription factor activated by glucose metabolites that orchestrates the expression of genes involved in glycolysis, <em>de novo</em> lipogenesis, and ATP homeostasis. Inadequate ChREBP activity impairs the cellular adaptations to glucose exposure and in humans associates with dyslipidemia, fatty liver disease, and type 2 diabetes. ChREBP activity is regulated by cytosolic-nuclear translocation involving its low-glucose inhibitory domain (LID). Whether this domain is targeted by post-translational lysine acetylation is unknown. Here we report a novel LID acetylation site that controls activity and protein interactions of ChREBP. Mutation of this residue increased glucose-induced activity and target gene expression of ChREBP. Mechanistically, mutant ChREBP protein showed more nuclear localization and enhanced genomic binding to a target promoter. Interactions with proteins that exhibit differential binding upon glucose exposure were attenuated by the mutation, demonstrating the importance of the LID in the formation of the protein interactome. Particularly interactions with 14-3-3 proteins, factors that regulate cytosolic/nuclear trafficking of ChREBP, were reduced, whereas interactions with proteins of the nucleosome remodeling deacetylase complex (NuRD) were increased. These molecular insights may shape new therapeutic strategies to target ChREBP activity and counteract metabolic diseases.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169189"},"PeriodicalIF":4.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951797","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

Decoding the Minimal Translation System of the Plasmodium falciparum Apicoplast: Essential tRNA-modifying Enzymes and Their Roles in Organelle Maintenance. 恶性疟原虫顶质体最小翻译系统的解码：必要的trna修饰酶及其在细胞器维持中的作用。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-06 DOI: 10.1016/j.jmb.2025.169156

Rubayet Elahi, Sebastian Mesones Mancilla, Montana L Sievert, Luciana Ribeiro Dinis, Opeoluwa Adewale-Fasoro, Alexis Mann, Yonatan Zur, Sean T Prigge

{"title":"Decoding the Minimal Translation System of the Plasmodium falciparum Apicoplast: Essential tRNA-modifying Enzymes and Their Roles in Organelle Maintenance.","authors":"Rubayet Elahi, Sebastian Mesones Mancilla, Montana L Sievert, Luciana Ribeiro Dinis, Opeoluwa Adewale-Fasoro, Alexis Mann, Yonatan Zur, Sean T Prigge","doi":"10.1016/j.jmb.2025.169156","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169156","url":null,"abstract":"<p><p>Post-transcriptional tRNA modifications are essential for accurate and efficient protein translation across all organisms. The apicoplast organelle genome of Plasmodium falciparum contains a minimal set of 25 complete tRNA isotypes, making it an ideal model for studying minimal translational machinery. Efficient decoding of mRNA codons by this limited tRNA set depends on post-transcriptional modifications. In this study, we sought to define the minimal set of tRNA-modifying enzymes. Using comparative genomics and apicoplast protein localization prediction tools, we identified 16 nucleus-encoded tRNA-modifying enzymes predicted to localize to the apicoplast. Experimental studies confirmed apicoplast localization for 14 enzymes, including two with dual localization. Combining an apicoplast metabolic bypass parasite line with gene disruption tools, we disrupted 12 of the 14 apicoplast-localized enzymes. Six of these enzymes were found to be essential for parasite survival, and six were dispensable. All six essential enzymes are thought to catalyze modifications in the anticodon loop of tRNAs, and their deletions resulted in apicoplast disruption. Of the two genes refractory to deletion, one exhibited dual localization, suggesting essential functions outside the apicoplast. The other, which appears to localize solely to the apicoplast, may play an indispensable role that is not circumvented by our metabolic bypass. Our findings suggest the apicoplast translation system relies on a minimal set of tRNA modifications concentrated in the anticodon loop. This work advances our understanding of minimal translational machinery in reduced organelles, such as the apicoplast, with promising applications in synthetic biology.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169156"},"PeriodicalIF":4.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955303","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

Structure of an Unfavorable de Novo DNA Methylation Complex of Plant Methyltransferase ZMET2 植物甲基转移酶ZMET2的不利从头DNA甲基化复合体的结构

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-05 DOI: 10.1016/j.jmb.2025.169186

Genevieve Herle , Jian Fang , Jikui Song

{"title":"Structure of an Unfavorable de Novo DNA Methylation Complex of Plant Methyltransferase ZMET2","authors":"Genevieve Herle , Jian Fang , Jikui Song","doi":"10.1016/j.jmb.2025.169186","DOIUrl":"10.1016/j.jmb.2025.169186","url":null,"abstract":"<div><div>DNA methylation is an important epigenetic mechanism that controls the assembly of heterochromatin and gene expression. In plants, DNA methylation occurs in both CG and non-CG contexts, with non-CG methylation showing notable substrate sequence dependence. The plant DNA methyltransferase CMT3 mediates maintenance of CHG (H = A, C, or T) DNA methylation, with a strong substrate preference for the hemimethylated CWG (W = A, T) motif. Yet, the underlying mechanism remains elusive. Here we present a crystal structure of ZMET2, the CMT3 ortholog from <em>Zea mays</em> (maize), in complex with a DNA substrate containing an unmethylated CTG motif and a histone peptide carrying a mimic of the histone H3K9me2 modification. Structural comparison of the ZMET2-CTG complex with the previously reported structure of ZMET2 bound to hemimethylated CAG DNA reveals similar but distinct protein-DNA interactions centered on the CWG motif, providing insight into the methylation state- and substrate sequence-specific ZMET2/CMT3-substrate interaction. Furthermore, our combined structural and biochemical analysis reveals a role for the +3-flanking base of the target cytosine in fine-tuning ZMET2-mediated DNA methylation and its functional interplay with the +1- and +2-flanking sites. Together, these results provide deep mechanistic insights into the substrate specificity of CMT3 DNA methyltransferases in plants.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169186"},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948820","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

Solution AFM Imaging and Coarse-grained Molecular Modeling of Yeast Condensin Structural Variation Coupled to the ATP Hydrolysis Cycle 溶液AFM成像和粗粒度分子模型酵母凝聚蛋白结构变化耦合到ATP水解循环。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-03 DOI: 10.1016/j.jmb.2025.169185

Hiroki Koide , Noriyuki Kodera , Shoji Takada , Tsuyoshi Terakawa

{"title":"Solution AFM Imaging and Coarse-grained Molecular Modeling of Yeast Condensin Structural Variation Coupled to the ATP Hydrolysis Cycle","authors":"Hiroki Koide , Noriyuki Kodera , Shoji Takada , Tsuyoshi Terakawa","doi":"10.1016/j.jmb.2025.169185","DOIUrl":"10.1016/j.jmb.2025.169185","url":null,"abstract":"<div><div>Condensin is a protein complex that regulates chromatin structural changes during mitosis. It varies the molecular conformation through the ATP hydrolysis cycle and extrudes DNA loops into its ring-like structure as a molecular motor. Condensin contains Smc2 and Smc4, in which a coiled-coil arm tethers the hinge and head domains and dimerizes at the hinge. ATPs bind between the heads, induce their engagement, and are hydrolyzed to promote their disengagement. Previously, we performed solution atomic force microscopy (AFM) imaging of yeast condensin holo-complex with ATP and conducted flexible molecular fitting, obtaining the hinge structure with open conformation. However, it has yet to be clarified how the opening/closing of the hinge is coupled to the ATP hydrolysis cycle. In this study, we performed solution AFM imaging in the presence and absence of varying nucleotides, including AMP-PNP, ATPγS, and ADP. Furthermore, we conducted molecular dynamics simulations of an Smc2/4 heterodimer and selected the structure best representing each AFM image. Our results suggested that head engagement upon ATP binding is coupled to hinge opening and that the N-terminal region of Brn1, one of the accessory subunits, re-associates to the Smc2 head after ADP release.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169185"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951645","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

A F420-dependent Single Domain Chemogenetic Tool for Protein De-dimerization 蛋白质去二聚化的f420依赖的单域化学发生工具。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-05-03 DOI: 10.1016/j.jmb.2025.169184

James Antoney , Stephanie Kainrath , Joshua G. Dubowsky , F.Hafna Ahmed , Suk Woo Kang , Emily R.R. Mackie , Gustavo Bracho Granado , Tatiana P. Soares da Costa , Colin J. Jackson , Harald Janovjak

{"title":"A F420-dependent Single Domain Chemogenetic Tool for Protein De-dimerization","authors":"James Antoney , Stephanie Kainrath , Joshua G. Dubowsky , F.Hafna Ahmed , Suk Woo Kang , Emily R.R. Mackie , Gustavo Bracho Granado , Tatiana P. Soares da Costa , Colin J. Jackson , Harald Janovjak","doi":"10.1016/j.jmb.2025.169184","DOIUrl":"10.1016/j.jmb.2025.169184","url":null,"abstract":"<div><div>Protein-protein interactions (PPIs) mediate many fundamental cellular processes. Control of PPIs through optically or chemically responsive protein domains has had a profound impact on basic research and some clinical applications. Most chemogenetic methods induce the association, i.e., dimerization or oligomerization, of target proteins, whilst the few available dissociation approaches either break large oligomeric protein clusters or heteromeric complexes. Here, we have exploited the controlled dissociation of a homodimeric oxidoreductase from mycobacteria (MSMEG_2027) by its native cofactor, F<sub>420</sub>, which is not present in mammals, as a bioorthogonal monomerization switch. Using X-ray crystallography, we found that in the absence of F<sub>420</sub> MSMEG_2027 forms a unique domain-swapped dimer that occludes the cofactor binding site. Rearrangement of the N-terminal helix upon F<sub>420</sub> binding results in the dissolution of the dimer. We then showed that MSMEG_2027 can be fused to proteins of interest in human cells and applied it as a tool to induce and release MAPK/ERK signalling downstream of a chimeric fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase. This F<sub>420</sub>-dependent chemogenetic de-homodimerization tool is stoichiometric and based on a single domain and thus represents a novel mechanism to investigate protein complexes <em>in situ</em>.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169184"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958135","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

Hepatitis B Virus Nucleocapsid Assembly. 乙型肝炎病毒核衣壳组装。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-30 DOI: 10.1016/j.jmb.2025.169182

Xupeng Hong, William M Schneider, Charles M Rice

{"title":"Hepatitis B Virus Nucleocapsid Assembly.","authors":"Xupeng Hong, William M Schneider, Charles M Rice","doi":"10.1016/j.jmb.2025.169182","DOIUrl":"10.1016/j.jmb.2025.169182","url":null,"abstract":"<p><p>Hepatitis B virus (HBV), the prototypical member of the Hepadnaviridae family, is a DNA virus that replicates its genome through reverse transcription of a pregenomic RNA (pgRNA) precursor. The selective packaging of pgRNA and viral polymerase (Pol) into assembling capsids formed by the viral core protein-a process known as nucleocapsid assembly-is an essential step in the HBV lifecycle. Advances in cellular and cell-free systems have provided significant insights into the mechanisms underlying capsid assembly, Pol binding to pgRNA, Pol-pgRNA packaging, and initiation of genome replication. However, the absence of a cell-free system capable of reconstituting selective HBV Pol-pgRNA packaging into fully assembled capsids leaves fundamental questions about nucleocapsid assembly unanswered. This review summarizes the current knowledge of HBV nucleocapsid assembly, focusing on the interplay between Pol-pgRNA interactions, capsid formation, and regulation by host factors. It also highlights the contribution of cellular and cell-free systems to these discoveries and underscores the need for new approaches that reconstitute the complete HBV nucleocapsid assembly process. With the growing interest in developing nucleocapsid assembly inhibitors, some of which are currently in clinical trials, targeting Pol-pgRNA interactions and nucleocapsid assembly represents a promising therapeutic strategy for curing chronic hepatitis B.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169182"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956772","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

Artificial-intelligence-driven Innovations in Mechanistic Computational Modeling and Digital Twins for Biomedical Applications. 生物医学应用中机械计算建模和数字孪生的人工智能驱动创新。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-30 DOI: 10.1016/j.jmb.2025.169181

Bhanwar Lal Puniya

{"title":"Artificial-intelligence-driven Innovations in Mechanistic Computational Modeling and Digital Twins for Biomedical Applications.","authors":"Bhanwar Lal Puniya","doi":"10.1016/j.jmb.2025.169181","DOIUrl":"10.1016/j.jmb.2025.169181","url":null,"abstract":"<p><p>Understanding of complex biological systems remains a significant challenge due to their high dimensionality, nonlinearity, and context-specific behavior. Artificial intelligence (AI) and mechanistic modeling are becoming essential tools for studying such complex systems. Mechanistic modeling can facilitate the construction of simulatable models that are interpretable but often struggle with scalability and parameters estimation. AI can integrate multi-omics data to create predictive models, but it lacks interpretability. The gap between these two modeling methods limits our ability to develop comprehensive and predictive models for biomedical applications. This article reviews the most recent advancements in the integration of AI and mechanistic modeling to fill this gap. Recently, with omics availability, AI has led to new discoveries in mechanistic computational modeling. The mechanistic models can also help in getting insight into the mechanism for prediction made by AI models. This integration is helpful in modeling complex systems, estimating the parameters that are hard to capture in experiments, and creating surrogate models to reduce computational costs because of expensive mechanistic model simulations. This article focuses on advancements in mechanistic computational models and AI models and their integration for scientific discoveries in biology, pharmacology, drug discovery and diseases. The mechanistic models with AI integration can facilitate biological discoveries to advance our understanding of disease mechanisms, drug development, and personalized medicine. The article also highlights the role of AI and mechanistic model integration in the development of more advanced models in the biomedical domain, such as medical digital twins and virtual patients for pharmacological discoveries.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169181"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957845","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

Deciphering Allosteric Modulation of Cancer-Associated Histone Missense Mutations. 解读癌症相关组蛋白错义突变的变构调节。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-29 DOI: 10.1016/j.jmb.2025.169180

Shuxiang Li, Jie Shu, James C Rober, Austin Macklem, Daniel Espiritu, Tanay Debnath, Samuel Tian, Daniel Tian, Maria J Aristizabal, Anna R Panchenko

{"title":"Deciphering Allosteric Modulation of Cancer-Associated Histone Missense Mutations.","authors":"Shuxiang Li, Jie Shu, James C Rober, Austin Macklem, Daniel Espiritu, Tanay Debnath, Samuel Tian, Daniel Tian, Maria J Aristizabal, Anna R Panchenko","doi":"10.1016/j.jmb.2025.169180","DOIUrl":"10.1016/j.jmb.2025.169180","url":null,"abstract":"<p><p>Histone mutations have been implicated in various cancers, but their mechanistic effects on chromatin dynamics remain largely unexplored. In this study, we investigated allosteric modulation effects induced by 40 cancer-associated histone missense mutations. By combining computational approaches with experimental evidence, we assessed the allosteric and functional impact of these mutations. Our results reveal that the allosteric effects of histone mutations are position-specific, with mutations near the H3 and H4 histone N-terminal tails exhibiting the strongest long-range perturbations. Notably, we predicted seven mutations with significant allosteric effects, potentially altering nucleosome interactions. Experimental verification of H2BS64Y and H2BS64F mutations demonstrated that they disrupted normal histone function, altered H2BK120 ubiquitination levels and genome stability, findings suggestive of their potential carcinogenic effects. Collectively, these results show that allostery may serve as a critical mechanism underlying the oncogenic potential of some histone mutations, highlighting the need for further exploration of allosteric pathways in cancer epigenetics.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169180"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962703","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

The Evolution of Sequence Specificity in a DNA Binding Protein Family DNA结合蛋白家族序列特异性的进化

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-29 DOI: 10.1016/j.jmb.2025.169177

Meghna Nandy , Madhumitha Krishnaswamy , Mohak Sharda , Aswin Sai Narain Seshasayee

{"title":"The Evolution of Sequence Specificity in a DNA Binding Protein Family","authors":"Meghna Nandy , Madhumitha Krishnaswamy , Mohak Sharda , Aswin Sai Narain Seshasayee","doi":"10.1016/j.jmb.2025.169177","DOIUrl":"10.1016/j.jmb.2025.169177","url":null,"abstract":"<div><div>Transcriptional regulation enables bacteria to adjust to its environment. This is driven by transcription factors (TFs), which display DNA site recognition specificity with some flexibility built in. TFs, however, are not considered essential to a minimal cellular life. How did they evolve? It has been hypothesized that TFs evolve by gaining specificity (and other functions) on a background of non-specific chromosome structuring proteins. We used the IHF/HU family of DNA binding proteins, in which IHF binds DNA in a sequence-specific manner, whereas HU binds more indiscriminately, to test this hypothesis. We show that HUβ has been present from the bacterial root, while both IHF subunits emerged much later and diversified in <em>Proteobacteria</em>, with HUα having possibly arisen from transfer events in <em>Gammaproteobacteria</em>. By reconstructing ancestral sequences <em>in-silico</em> on a rooted phylogeny of IHF/HU we show that the common ancestor of this family was probably HU-like and therefore non-specific in binding DNA. IHF evolved from a branch of HU after HU had substantially diverged. Various residues characteristic of IHFα and shown to be involved in specific sequence recognition (at least in <em>E. coli</em>) have likely been co-opted from preexisting residues in HU, while those residues of IHFβ have likely evolved independently, suggesting that each of the IHF subunits has undergone different trajectories to acquire their DNA binding properties.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 14","pages":"Article 169177"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924349","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