Pub Date : 2026-01-16DOI: 10.1016/j.jmb.2026.169644
Samuel Schwab, Michel Olsthoorn, Tim Jansen, Remus T Dame
Histones are one of the fundamental chromatin proteins of life. In eukaryotes and megaviruses, they form nucleosome structures that wrap DNA. However, in prokaryotes, histones are much more diverse in how they organize DNA. In bacteria, histones bend and wrap DNA while in archaea they wrap and bridge DNA. These differences in DNA organizing properties are primarily due to distinct modes of histone multimerization. Here we present ProHistoneDB, an online database describing and categorizing prokaryotic and viral histones. For each histone, monomer, dimer, tetramer, and hexamer predictions are viewable and downloadable. ProHistoneDB contains 7334 histones, categorized into 24 groups based on the multimer predictions. For each category, interactive phylogenetic trees and HMM profile logos are available to identify conserved residues and explore the relative evolutionary relationships of histones. ProHistoneDB can be accessed at https://prohistonedb.org/.
{"title":"ProHistoneDB: A database of prokaryotic and viral histones.","authors":"Samuel Schwab, Michel Olsthoorn, Tim Jansen, Remus T Dame","doi":"10.1016/j.jmb.2026.169644","DOIUrl":"10.1016/j.jmb.2026.169644","url":null,"abstract":"<p><p>Histones are one of the fundamental chromatin proteins of life. In eukaryotes and megaviruses, they form nucleosome structures that wrap DNA. However, in prokaryotes, histones are much more diverse in how they organize DNA. In bacteria, histones bend and wrap DNA while in archaea they wrap and bridge DNA. These differences in DNA organizing properties are primarily due to distinct modes of histone multimerization. Here we present ProHistoneDB, an online database describing and categorizing prokaryotic and viral histones. For each histone, monomer, dimer, tetramer, and hexamer predictions are viewable and downloadable. ProHistoneDB contains 7334 histones, categorized into 24 groups based on the multimer predictions. For each category, interactive phylogenetic trees and HMM profile logos are available to identify conserved residues and explore the relative evolutionary relationships of histones. ProHistoneDB can be accessed at https://prohistonedb.org/.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169644"},"PeriodicalIF":4.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996979","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}
Pub Date : 2026-01-14DOI: 10.1016/j.jmb.2026.169641
Emma L. Sedivy, Emily Agnello , Julia E. Hobaugh, Rakeyah Ahsan, Kangkang Song , Chen Xu, Brian A. Kelch
Viruses assemble from component parts inside their host cells, but the mechanisms coordinating this complex process are not completely understood. In tailed bacteriophages, the genome is packaged into its capsid shell through the portal complex. The portal complex then closes to retain DNA and connects to the tail, which is required for host recognition and infection. The trigger to stop pumping DNA and assemble the mature virus has been a longstanding conundrum in the field. We determined the structure of the portal, the proteins that connect it to the tail, and portal vertex in the hyperthermophilic phage Oshimavirus using cryo-Electron Microscopy (cryo-EM). We find highly intertwined loop structures, like in a wicker basket, potentially stabilizing the portal vertex against high temperatures. Moreover, we observe that the portal protrudes from the capsid in mature virions. We propose that portal is repositioned by packaged DNA, forming a pressure-sensitive switch that terminates genome packaging and triggers tail attachment in headful phages.
{"title":"The Structure of a Thermostable Phage’s Portal Vertex and Neck Complex Illuminates the Headful Maturation Mechanism","authors":"Emma L. Sedivy, Emily Agnello , Julia E. Hobaugh, Rakeyah Ahsan, Kangkang Song , Chen Xu, Brian A. Kelch","doi":"10.1016/j.jmb.2026.169641","DOIUrl":"10.1016/j.jmb.2026.169641","url":null,"abstract":"<div><div>Viruses assemble from component parts inside their host cells, but the mechanisms coordinating this complex process are not completely understood. In tailed bacteriophages, the genome is packaged into its capsid shell through the portal complex. The portal complex then closes to retain DNA and connects to the tail, which is required for host recognition and infection. The trigger to stop pumping DNA and assemble the mature virus has been a longstanding conundrum in the field. We determined the structure of the portal, the proteins that connect it to the tail, and portal vertex in the hyperthermophilic phage Oshimavirus using cryo-Electron Microscopy (cryo-EM). We find highly intertwined loop structures, like in a wicker basket, potentially stabilizing the portal vertex against high temperatures. Moreover, we observe that the portal protrudes from the capsid in mature virions. We propose that portal is repositioned by packaged DNA, forming a pressure-sensitive switch that terminates genome packaging and triggers tail attachment in headful phages.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169641"},"PeriodicalIF":4.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987641","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}
Pub Date : 2026-01-14DOI: 10.1016/j.jmb.2026.169638
William R.K. Talley , Daniel Bazan , Jaroslaw Majewski , Herbert Kaltner , Crystal M. Vander Zanden
Tandem-repeat galectins are a family of proteins containing two carbohydrate recognition domains (CRDs) with affinity to various glycoproteins and glycolipids involved in cell signaling. Galectin-4 is expressed in intestinal epithelial cells, and galectin-8 is essential in regulating cell adhesion and immune response. Misregulation of both tandem-repeat galectins is linked to variable cancer cell behavior. Structure models for the membrane-bound forms of galectin-4 and galectin-8 were constructed from X-ray reflectivity measurements coupled with molecular dynamics for galectin-4. The proteins were bound to lipid monolayers containing their respective ligands, gangliosides GM1 or GM3, to determine the membrane-bound structure. Galectin-4 contains two CRDs with weak affinity for GM1, and it bound with both CRDs arranged near the membrane while dynamically sampling alternative conformations. Galectin-8, in contrast, contains only one CRD with tight binding to GM3, and one CRD was pointed towards the membrane while the other oriented away from the membrane. Shortening the peptide linker between the CRDs altered protein binding to the membrane, suggesting the linker likely facilitates stabilizing contacts between the CRDs. Overall, this work helps to illustrate the conformational dynamics of tandem-repeat galectins, emphasizing the roles of ligand affinity, linker peptide dynamics, and contacts between CRDs.
{"title":"Structure of Two Tandem-Repeat Galectin Proteins Binding a Model Glycolipid Membrane","authors":"William R.K. Talley , Daniel Bazan , Jaroslaw Majewski , Herbert Kaltner , Crystal M. Vander Zanden","doi":"10.1016/j.jmb.2026.169638","DOIUrl":"10.1016/j.jmb.2026.169638","url":null,"abstract":"<div><div>Tandem-repeat galectins are a family of proteins containing two carbohydrate recognition domains (CRDs) with affinity to various glycoproteins and glycolipids involved in cell signaling. Galectin-4 is expressed in intestinal epithelial cells, and galectin-8 is essential in regulating cell adhesion and immune response. Misregulation of both tandem-repeat galectins is linked to variable cancer cell behavior. Structure models for the membrane-bound forms of galectin-4 and galectin-8 were constructed from X-ray reflectivity measurements coupled with molecular dynamics for galectin-4. The proteins were bound to lipid monolayers containing their respective ligands, gangliosides GM1 or GM3, to determine the membrane-bound structure. Galectin-4 contains two CRDs with weak affinity for GM1, and it bound with both CRDs arranged near the membrane while dynamically sampling alternative conformations. Galectin-8, in contrast, contains only one CRD with tight binding to GM3, and one CRD was pointed towards the membrane while the other oriented away from the membrane. Shortening the peptide linker between the CRDs altered protein binding to the membrane, suggesting the linker likely facilitates stabilizing contacts between the CRDs. Overall, this work helps to illustrate the conformational dynamics of tandem-repeat galectins, emphasizing the roles of ligand affinity, linker peptide dynamics, and contacts between CRDs.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169638"},"PeriodicalIF":4.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987685","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}
Pub Date : 2026-01-14DOI: 10.1016/j.jmb.2026.169640
Xin Li , Nan Liu , Kaiyu Gao , Carina Muyao Gu , Zhihao Cui , Kundi Zhang , Sujuan Xu , Lichuan Gu
Streptococcus mutans, the major causative agent of dental plaque and caries, maintains osmotic balance under hyperosmotic conditions by transporting glycine betaine into the cytoplasm via the BusAB transporter system. This mechanism is coordinated by the c-di-AMP-responsive transcriptional regulator BusR, which represses busAB expression in the absence of osmotic stress. In this study, we systematically characterized the function of BusR in S. mutans UA159. Our experiments showed that deletion of busR resulted not only in high expression of busAB but also in upregulated GlcNAc metabolic genes, specifically nagA/nagB and glmS, which are known to be regulated by transcriptional regulator NagR. The ΔbusR strain utilized GlcNAc as a nutrient more efficiently and exhibited a faster growth rate than the wild-type strain. Combined with results from further experimentation, this suggests that, BusR assumes a dual regulatory role under high-osmolarity conditions: it relieves repression of busAB to increase the transport of the osmoprotectant betaine into cytoplasm, and cooperates with NagR to regulate amino sugar metabolism by regulating the transcription of nagA/nagB and glmS. Consistent with the molecular ruler mechanism previously described for BusR homologs from Streptococcus agalactiae, we observe a similar structural basis that enables BusR to mediate precise, c-di-AMP–dependent modulation of gene transcription. This coordinated regulation of osmoprotection and amino sugar metabolism by BusR may give S. mutans a significant advantage for dealing with osmotic stress within the oral environment.
{"title":"BusR is a Bifunctional Transcription Factor Coordinating Both Osmotic Response and Amino Sugar Metabolism in Streptococcus mutans","authors":"Xin Li , Nan Liu , Kaiyu Gao , Carina Muyao Gu , Zhihao Cui , Kundi Zhang , Sujuan Xu , Lichuan Gu","doi":"10.1016/j.jmb.2026.169640","DOIUrl":"10.1016/j.jmb.2026.169640","url":null,"abstract":"<div><div><em>Streptococcus mutans,</em> the major causative agent of dental plaque and caries, maintains osmotic balance under hyperosmotic conditions by transporting glycine betaine into the cytoplasm via the BusAB transporter system. This mechanism is coordinated by the c-di-AMP-responsive transcriptional regulator BusR, which represses <em>busAB</em> expression in the absence of osmotic stress. In this study, we systematically characterized the function of BusR in <em>S. mutans</em> UA159. Our experiments showed that deletion of <em>busR</em> resulted not only in high expression of <em>busAB</em> but also in upregulated GlcNAc metabolic genes, specifically <em>nagA/nagB</em> and <em>glmS</em>, which are known to be regulated by transcriptional regulator NagR. The Δ<em>busR</em> strain utilized GlcNAc as a nutrient more efficiently and exhibited a faster growth rate than the wild-type strain. Combined with results from further experimentation, this suggests that, BusR assumes a dual regulatory role under high-osmolarity conditions: it relieves repression of <em>busAB</em> to increase the transport of the osmoprotectant betaine into cytoplasm, and cooperates with NagR to regulate amino sugar metabolism by regulating the transcription of <em>nagA/nagB</em> and <em>glmS</em>. Consistent with the molecular ruler mechanism previously described for BusR homologs from <em>Streptococcus agalactiae</em>, we observe a similar structural basis that enables BusR to mediate precise, c-di-AMP–dependent modulation of gene transcription. This coordinated regulation of osmoprotection and amino sugar metabolism by BusR may give <em>S. mutans</em> a significant advantage for dealing with osmotic stress within the oral environment.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169640"},"PeriodicalIF":4.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987699","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}
Pub Date : 2026-01-12DOI: 10.1016/j.jmb.2026.169639
Igor N Berezovsky, Ruth Nussinov
{"title":"From Extreme Environments in Nature to Molecular and Cellular Adaptation and Functional Regulation.","authors":"Igor N Berezovsky, Ruth Nussinov","doi":"10.1016/j.jmb.2026.169639","DOIUrl":"10.1016/j.jmb.2026.169639","url":null,"abstract":"","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169639"},"PeriodicalIF":4.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984203","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}
Pub Date : 2026-01-09DOI: 10.1016/j.jmb.2026.169634
Sheng-Cai Lin
My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose, which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD+, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8+ T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a “chosen” molecule.
{"title":"Pioneers: Glucose Sensing and Control of Health-span and Lifespan","authors":"Sheng-Cai Lin","doi":"10.1016/j.jmb.2026.169634","DOIUrl":"10.1016/j.jmb.2026.169634","url":null,"abstract":"<div><div>My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose, which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD<sup>+</sup>, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8<sup>+</sup> T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a “chosen” molecule.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169634"},"PeriodicalIF":4.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951111","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}
Pub Date : 2026-01-09DOI: 10.1016/j.jmb.2026.169633
Weimin Lu, Yintao Zhang, Kuerbannisha Amahong, Sisi Zhu, Xiuwen Li, Ying Zhou, Feng Zhu, Lin Tao
The ongoing evolution of coronaviruses (CoVs) poses a long-term threat to global public health, requiring dissection of virus-host interactions to develop broad-spectrum antivirals. Existing data resources are often limited to specific interaction types, hindering a systematic understanding of the complete viral life cycle. To address this, CovInter 2.0 (https://idrblab.org/COVINTER) has been developed as a comprehensively upgraded database of coronavirus interactomics, which is the first to systematically integrate the six major classes of molecular interactions that drive the viral life cycle, compiling over 61,000 entries. Furthermore, data for 229 potential anti-CoV drugs and their targets have been included, bridging molecular interactions with therapeutic development. The platform features an interactive network visualization tool for intuitive exploration of these complex relationships. As an open-access resource, CovInter 2.0 provides a powerful tool for virology and drug discovery, computational biology, designed to accelerate the identification of novel antiviral targets and the development of next-generation therapeutics.
{"title":"CovInter 2.0: Comprehensive Molecular Interactome of Coronavirus Infection.","authors":"Weimin Lu, Yintao Zhang, Kuerbannisha Amahong, Sisi Zhu, Xiuwen Li, Ying Zhou, Feng Zhu, Lin Tao","doi":"10.1016/j.jmb.2026.169633","DOIUrl":"10.1016/j.jmb.2026.169633","url":null,"abstract":"<p><p>The ongoing evolution of coronaviruses (CoVs) poses a long-term threat to global public health, requiring dissection of virus-host interactions to develop broad-spectrum antivirals. Existing data resources are often limited to specific interaction types, hindering a systematic understanding of the complete viral life cycle. To address this, CovInter 2.0 (https://idrblab.org/COVINTER) has been developed as a comprehensively upgraded database of coronavirus interactomics, which is the first to systematically integrate the six major classes of molecular interactions that drive the viral life cycle, compiling over 61,000 entries. Furthermore, data for 229 potential anti-CoV drugs and their targets have been included, bridging molecular interactions with therapeutic development. The platform features an interactive network visualization tool for intuitive exploration of these complex relationships. As an open-access resource, CovInter 2.0 provides a powerful tool for virology and drug discovery, computational biology, designed to accelerate the identification of novel antiviral targets and the development of next-generation therapeutics.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169633"},"PeriodicalIF":4.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951080","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}
Pub Date : 2026-01-08DOI: 10.1016/j.jmb.2026.169635
Aiming Ren
Aiming Ren obtained her Ph.D. in Structural Biology and Chemical Biology from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and conducted postdoctoral research at the Memorial Sloan Kettering Cancer Center, where she investigated RNA molecules involved in gene expression regulation (riboswitches) and self-cleavage catalysis (ribozymes). Ren later established her independent laboratory at Zhejiang University, focusing on the structural and mechanistic understanding of functional RNAs—particularly riboswitches, self-cleaving ribozymes, and RNA fluorogenic aptamers (FLAP). These RNA molecules represent elegant examples of RNA nature’s regulatory, catalytic, and fluorescence activation strategies, performing precise chemical transformations and sophisticated functional control through dynamic structural rearrangements. The Ren laboratory combines biochemical and molecular biological approaches with high-resolution structural techniques, including X-ray crystallography and cryo-electron microscopy, to elucidate how RNA architectures encode regulatory, catalytic, and activation functions. Through systematic investigations, Ren and her team have explored how riboswitches couple ligand recognition to gene regulation via dynamic conformational shifts, uncovered the catalytic mechanisms of several newly discovered self-cleaving ribozymes, revealing both shared structural principles and unique chemical strategies underlying RNA self-scission. The group also investigated how RNA aptamers fold to stabilize the bound dyes and enhance their fluorescence by several thousand-fold. By bridging RNA chemistry, structure, and dynamics, Aiming Ren’s research aims to illuminate the fundamental principles governing RNA function and evolution. Her work provides deep insights into RNA-based regulation, catalysis, and fluorescence activation, offering important implications for understanding ancient biochemical systems and for the development of novel RNA-based tools and therapeutics.
{"title":"Rising Star: Folding Pattern and Working Mechanism of Functional RNA Molecules","authors":"Aiming Ren","doi":"10.1016/j.jmb.2026.169635","DOIUrl":"10.1016/j.jmb.2026.169635","url":null,"abstract":"<div><div><strong>Aiming Ren</strong> obtained her Ph.D. in Structural Biology and Chemical Biology from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and conducted postdoctoral research at the Memorial Sloan Kettering Cancer Center, where she investigated RNA molecules involved in gene expression regulation (riboswitches) and self-cleavage catalysis (ribozymes). Ren later established her independent laboratory at Zhejiang University, focusing on the structural and mechanistic understanding of functional RNAs—particularly riboswitches, self-cleaving ribozymes, and RNA fluorogenic aptamers (FLAP). These RNA molecules represent elegant examples of RNA nature’s regulatory, catalytic, and fluorescence activation strategies, performing precise chemical transformations and sophisticated functional control through dynamic structural rearrangements. The Ren laboratory combines biochemical and molecular biological approaches with high-resolution structural techniques, including X-ray crystallography and cryo-electron microscopy, to elucidate how RNA architectures encode regulatory, catalytic, and activation functions. Through systematic investigations, Ren and her team have explored how riboswitches couple ligand recognition to gene regulation via dynamic conformational shifts, uncovered the catalytic mechanisms of several newly discovered self-cleaving ribozymes, revealing both shared structural principles and unique chemical strategies underlying RNA self-scission. The group also investigated how RNA aptamers fold to stabilize the bound dyes and enhance their fluorescence by several thousand-fold. By bridging RNA chemistry, structure, and dynamics, Aiming Ren’s research aims to illuminate the fundamental principles governing RNA function and evolution. Her work provides deep insights into RNA-based regulation, catalysis, and fluorescence activation, offering important implications for understanding ancient biochemical systems and for the development of novel RNA-based tools and therapeutics.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169635"},"PeriodicalIF":4.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948274","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}
Pub Date : 2026-01-07DOI: 10.1016/j.jmb.2026.169630
Yunhe Tian, Ziyu Li, Jialin Yang, Jianwei Li
Long non-coding RNAs (lncRNAs) regulate gene expression, cellular functions, and disease-related processes through extensive and diverse interactions with various molecules, thereby forming heterogeneous functional regulatory networks. LncRNAs often exert their regulatory effects in a cooperative manner, functional enrichment analysis is considered a powerful approach for systematically elucidating their functions. However, most existing methods focus on the functions of individual lncRNAs, overlooking complex interactions among them, which limits the scope of enrichment analysis. In this paper, we developed TLSEA 2.0 (http://www.lirmed.com/tlsea2/), an updated web-based tool with an expanded repository of functional lncRNA sets, for enhancing enrichment analysis capabilities. Compared with the earlier version of TLSEA, TLSEA 2.0 has tripled its reference lncRNA sets and expanded enrichment analysis categories from one to five: Disease, Drug, RNA-RNA Interaction, RNA-Protein Interaction, and Cancer Phenotype. TLSEA 2.0 introduces an Expansion option, which extends the user-submitted lncRNA list by incorporating additional lncRNAs that exhibit strong association with the input set based on similarity networks, thereby expanding the user-submitted lncRNA list and enabling the discovery of more potential associations. Additional functional similarity networks have been incorporated, including lncRNA-protein interactions and co-expression data. Furthermore, TLSEA 2.0 employs combining Graph Attention Networks (GAT) and Graph Convolutional Networks (GCN) to replace traditional graph representation learning during the process of extracting lncRNA features. These enhancements make TLSEA 2.0 a more comprehensive and robust online platform for functional enrichment analysis, facilitating deeper insights into the complex biological regulatory functions of lncRNAs.
{"title":"TLSEA 2.0: an updated tool for lncRNA enrichment analysis.","authors":"Yunhe Tian, Ziyu Li, Jialin Yang, Jianwei Li","doi":"10.1016/j.jmb.2026.169630","DOIUrl":"10.1016/j.jmb.2026.169630","url":null,"abstract":"<p><p>Long non-coding RNAs (lncRNAs) regulate gene expression, cellular functions, and disease-related processes through extensive and diverse interactions with various molecules, thereby forming heterogeneous functional regulatory networks. LncRNAs often exert their regulatory effects in a cooperative manner, functional enrichment analysis is considered a powerful approach for systematically elucidating their functions. However, most existing methods focus on the functions of individual lncRNAs, overlooking complex interactions among them, which limits the scope of enrichment analysis. In this paper, we developed TLSEA 2.0 (http://www.lirmed.com/tlsea2/), an updated web-based tool with an expanded repository of functional lncRNA sets, for enhancing enrichment analysis capabilities. Compared with the earlier version of TLSEA, TLSEA 2.0 has tripled its reference lncRNA sets and expanded enrichment analysis categories from one to five: Disease, Drug, RNA-RNA Interaction, RNA-Protein Interaction, and Cancer Phenotype. TLSEA 2.0 introduces an Expansion option, which extends the user-submitted lncRNA list by incorporating additional lncRNAs that exhibit strong association with the input set based on similarity networks, thereby expanding the user-submitted lncRNA list and enabling the discovery of more potential associations. Additional functional similarity networks have been incorporated, including lncRNA-protein interactions and co-expression data. Furthermore, TLSEA 2.0 employs combining Graph Attention Networks (GAT) and Graph Convolutional Networks (GCN) to replace traditional graph representation learning during the process of extracting lncRNA features. These enhancements make TLSEA 2.0 a more comprehensive and robust online platform for functional enrichment analysis, facilitating deeper insights into the complex biological regulatory functions of lncRNAs.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169630"},"PeriodicalIF":4.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941977","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}
Pub Date : 2026-01-07DOI: 10.1016/j.jmb.2026.169636
Jimin Pei, Jing Zhang, Qian Cong
Intrinsically disordered regions (IDRs) in proteins play a pivotal role in protein–protein interactions (PPIs). Using AlphaFold2 and enriched multiple sequence alignments, we predicted and investigated PPIs across the human proteome, focusing on those involving disordered regions. Our predictions show that disordered regions predominantly interact with ordered domains, whereas predicted disordered–disordered interactions are relatively rare. Although disordered regions typically lack annotated domains, certain regions—such as the keratin type II head domain and the Krüppel-associated box (KRAB)—mediate specific interactions. In contrast, their predicted binding partners frequently feature diverse Pfam domains, including protein kinase, WD40 repeat, and nuclear hormone receptor domains. These domains are enriched in nuclear localization and α-helical repeat motifs. Disordered regions involved in predicted PPIs exhibit higher sequence conservation than non-interacting disordered regions, suggesting evolutionary constraints at interaction interfaces. Moreover, certain posttranslational modifications (e.g., phosphorylation and acetylation) in disordered regions are enriched within predicted interaction interfaces, likely modulating binding affinities. Notably, we identified a significant enrichment of disease-associated mutations in predicted PPI interfaces involving disordered regions, underscoring their functional and pathological relevance. Together, these findings highlight the intricate interplay between disordered and ordered regions in mediating PPIs and provide insights into their structural and functional contributions to human health and disease.
{"title":"A Survey of Predicted Protein–Protein Interactions Involving Disordered Regions in Humans","authors":"Jimin Pei, Jing Zhang, Qian Cong","doi":"10.1016/j.jmb.2026.169636","DOIUrl":"10.1016/j.jmb.2026.169636","url":null,"abstract":"<div><div>Intrinsically disordered regions (IDRs) in proteins play a pivotal role in protein–protein interactions (PPIs). Using AlphaFold2 and enriched multiple sequence alignments, we predicted and investigated PPIs across the human proteome, focusing on those involving disordered regions. Our predictions show that disordered regions predominantly interact with ordered domains, whereas predicted disordered–disordered interactions are relatively rare. Although disordered regions typically lack annotated domains, certain regions—such as the keratin type II head domain and the Krüppel-associated box (KRAB)—mediate specific interactions. In contrast, their predicted binding partners frequently feature diverse Pfam domains, including protein kinase, WD40 repeat, and nuclear hormone receptor domains. These domains are enriched in nuclear localization and α-helical repeat motifs. Disordered regions involved in predicted PPIs exhibit higher sequence conservation than non-interacting disordered regions, suggesting evolutionary constraints at interaction interfaces. Moreover, certain posttranslational modifications (e.g., phosphorylation and acetylation) in disordered regions are enriched within predicted interaction interfaces, likely modulating binding affinities. Notably, we identified a significant enrichment of disease-associated mutations in predicted PPI interfaces involving disordered regions, underscoring their functional and pathological relevance. Together, these findings highlight the intricate interplay between disordered and ordered regions in mediating PPIs and provide insights into their structural and functional contributions to human health and disease.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169636"},"PeriodicalIF":4.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941994","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}