Journal of Molecular Biology最新文献_第9页

Domain Interactions in a Chimeric Dual-domain Lysin Lead to Broad Bactericidal Activity 嵌合双结构域溶酶的结构域相互作用导致广泛的杀菌活性。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-08-05 DOI: 10.1016/j.jmb.2025.169373

Fen Hu , Xiaomei Zhang , Zhou Gong , Pei Wu , Qun Zhao , Yuyan Zheng , Hang Gao , Shan-Ho Chou , Xinfeng Li , Mingyue Zhong , Zirong Zhao , Ning Shi , Hongping Wei , Jin He , Hang Yang

{"title":"Domain Interactions in a Chimeric Dual-domain Lysin Lead to Broad Bactericidal Activity","authors":"Fen Hu , Xiaomei Zhang , Zhou Gong , Pei Wu , Qun Zhao , Yuyan Zheng , Hang Gao , Shan-Ho Chou , Xinfeng Li , Mingyue Zhong , Zirong Zhao , Ning Shi , Hongping Wei , Jin He , Hang Yang","doi":"10.1016/j.jmb.2025.169373","DOIUrl":"10.1016/j.jmb.2025.169373","url":null,"abstract":"<div><div>Phage-derived lysins represent a novel, non-traditional therapeutic agent against multidrug-resistant bacteria. However, engineering lysins with broad host range remain poorly addressed. Previously, we reported that the chimeric lysin ClyR, which harbors the CHAP catalytic domain of PlyC lysin (PlyCAC) and the SH3b cell-wall binding domain of PlySs2 lysin (PlySb), exhibits an expanded host range<em>.</em> However, the mechanism by which ClyR exhibits expanded bactericidal activity is still not fully understood. Since the structure of PlyCAC is publicly available (PDB code: 4F88), here, we first solve the crystal structure of PlySb using X-ray diffraction, and then use various biophysical methods, such as X-ray diffraction, cross-linking coupled mass spectrometry (CXMS), and small-angle X-ray scattering (SAXS) to analyze the potential full-length structures of ClyR. Our results demonstrate that ClyR exhibits a dynamic conformation supported by multiple inter-domain interactions between the two constituent domains. Mutagenesis and biochemical analysis further support the notion that these inter-domain interactions may modulate the bactericidal activity of ClyR. Altogether, our findings provide novel insights into the action mechanism of ClyR and a better understanding of how inter-domain interactions influence the host range of chimeric lysins.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 21","pages":"Article 169373"},"PeriodicalIF":4.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793171","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

Comparative Study of a Variant Neural Relational Inference Deep Learning Model and Dynamical Network Analysis for p53-DNA Allosteric Interactions 变异神经关系推理深度学习模型与p53-DNA变构相互作用动态网络分析的比较研究。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-08-05 DOI: 10.1016/j.jmb.2025.169374

Haoxin Sun , Jingbo Wei , Yiming Tang , Tianjing Guo , Guanghong Wei , Jiangtao Lei

{"title":"Comparative Study of a Variant Neural Relational Inference Deep Learning Model and Dynamical Network Analysis for p53-DNA Allosteric Interactions","authors":"Haoxin Sun , Jingbo Wei , Yiming Tang , Tianjing Guo , Guanghong Wei , Jiangtao Lei","doi":"10.1016/j.jmb.2025.169374","DOIUrl":"10.1016/j.jmb.2025.169374","url":null,"abstract":"<div><div>Protein allostery is a critical regulatory mechanism in various biological processes, representing a challenging aspect of biological research. Dynamical network analysis serves as a foundational computational methodology for studying allosteric effects, while the recent emergence of neural relational inference (NRI) model has introduced novel insights into understanding it. In this study, we modified NRI model by integrating the multi-head self-attention module of transformer, and then compared the variant model with dynamical network analysis and initial NRI model for p53-DNA allosteric interactions. Our results show that the variant model is more focused on long-range allosteric than dynamical network in predicting p53-DNA allosteric pathways, and enhances superior accuracy and comprehensiveness compared to initial NRI model. Moreover, divergent allosteric pathways in wild-type (WT) versus mutant (MT) p53 may underlie their substantially different DNA recognition and binding behaviors. Finally, we found that even with undefined ending nodes, allosteric pathways consistently propagate from mutation sites toward DNA, and the length of pathways in MT p53 is significantly longer than that of WT p53. These suggest that mutation sites impair long-range allosteric communication, potentially disrupting signal transmission efficiency. Our results offer novel insights for a deep understanding of protein allosteric pathways through different methods.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 21","pages":"Article 169374"},"PeriodicalIF":4.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793170","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

From Science to Fiction - Connecting In Vivo and In Vitro Results in Polyprotein Processing of Coronaviruses. 从科学到虚构——体内和体外的连接导致冠状病毒的多蛋白加工。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-08-05 DOI: 10.1016/j.jmb.2025.169370

Kira Schamoni-Kast, Charlotte Uetrecht

{"title":"From Science to Fiction - Connecting In Vivo and In Vitro Results in Polyprotein Processing of Coronaviruses.","authors":"Kira Schamoni-Kast, Charlotte Uetrecht","doi":"10.1016/j.jmb.2025.169370","DOIUrl":"10.1016/j.jmb.2025.169370","url":null,"abstract":"<p><p>Polyprotein processing is a common strategy in many positive sense single-stranded RNA ((+)ssRNA) viruses. This highly regulated process is crucial for viral progeny and ensures the release of functional replicase proteins in the correct location and at the right time. Coronaviruses (CoVs) have one of the largest genomes on average among (+)ssRNA viruses requiring a unique replication-transcription complex (RTC) with proofreading function that prevents error catastrophe. Two thirds of the CoV genome encode for the non-structural proteins (nsps) that drive replication. These are directly synthesized by RNA genome translation after infection as two large polyproteins pp1a and pp1ab. A regulated polyprotein proteolytic auto-processing is essential for viral growth and always has been an interesting target for therapeutics. Here, we present an overview of polyprotein processing and RTC research in CoVs in vitro and in vivo over the last 30 years. We highlight cutting-edge methodologies such as super resolution microscopy or structural mass spectrometry approaches and demonstrate how these have contributed to polyprotein research, e.g. by providing comprehensive structural models. We illustrate exciting examples of polyprotein processing in other viruses that could be transferred to CoVs, too. Additionally, we identify critical knowledge gaps in polyprotein processing and RTC assembly, proposing future perspectives to address these limitations.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169370"},"PeriodicalIF":4.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774474","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

Corrigendum to “5-Methyluridine is Ubiquitous in Pseudomonas aeruginosa tRNA and Modulates Antimicrobial Resistance and Virulence” [J. Mol. Biol. 437(16) (2025) 169020] 5-甲基尿嘧啶在铜绿假单胞菌tRNA中普遍存在并调节抗菌素耐药性和毒力[J]。Mol. Biol. 437(16) (2025) 169020]

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-08-02 DOI: 10.1016/j.jmb.2025.169363

Jurairat Chittrakanwong , Ruixi Chen , Junzhou Wu , Michael S. Demott , Jingjing Sun , Kamonwan Phatinuwat , Juthamas Jaroensuk , Sopapan Atichartpongkul , Skorn Mongkolsuk , Thomas Begley , Peter C. Dedon , Mayuree Fuangthong

引用次数: 0

Corrigendum to “Conformational Transformation and Selection of Synthetic Prion Strains” [J. Mol. Biol. 413(3) (2011) 527–542] “合成朊病毒株的构象转化和选择”的勘误[J]。Mol. Biol. 413(3) (2011) 527-542]

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-08-01 DOI: 10.1016/j.jmb.2025.169353

Sina Ghaemmaghami , Joel C. Watts , Hoang-Oanh Nguyen , Shigenari Hayashi , Stephen J. DeArmond , Stanley B. Prusiner

引用次数: 0

25 Years of Ebola Virus VP35 Research 埃博拉病毒VP35研究25年。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-07-31 DOI: 10.1016/j.jmb.2025.169366

Grace Uwase , Daisy W. Leung , Gaya K. Amarasinghe

引用次数: 0

Rethinking Cellular Organization: Phase Separation as a Unifying Principle in Molecular Biology. 重新思考细胞组织：相分离是分子生物学的统一原则。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-07-31 DOI: 10.1016/j.jmb.2025.169367

Michael P Hughes

{"title":"Rethinking Cellular Organization: Phase Separation as a Unifying Principle in Molecular Biology.","authors":"Michael P Hughes","doi":"10.1016/j.jmb.2025.169367","DOIUrl":"10.1016/j.jmb.2025.169367","url":null,"abstract":"<p><p>Dimerization, liquid-liquid condensate formation, and amyloid deposition are all examples of macromolecular assembly and phase transitions essential for healthy cellular function but that become dysregulated in disease. A common underlying mechanism in these transitions is the dehydration of macromolecule surfaces. Through this lens, a deeper understanding emerges of how changing solvent conditions (e.g., solvent polarity, temperature, pH) affect the intracellular solubility of macromolecules. The cell cycle can be reframed as a cyclical change in solvent conditions, which, at an atomic scale, corresponds to the cyclical precipitation and solubilization of nucleic acid-binding proteins interacting with RNA or DNA. To solubilize nucleic acid-binding proteins, a negative counterion is required to pair with the Lysine/Arginine cations. ATP is the primary intracellular counterion, linking solubilization and precipitation dynamics directly to cellular metabolism. This framework highlights how cellular, in vivo conditions vary dramatically across time and space, revealing complexities that in vitro experiments often fail to capture. Recent advances in understanding these cyclical solvent-driven transitions are crucial to furthering progress in cell biology.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169367"},"PeriodicalIF":4.5,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768236","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

To What Extent is Anfinsen's Thermodynamic Hypothesis Consistent With the Formation and Polymorphism of Amyloid Fibrils? 安芬森的热力学假说在多大程度上符合淀粉样原纤维的形成和多态性？

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-07-30 DOI: 10.1016/j.jmb.2025.169364

Yi Xiao Jiang, David S Eisenberg

{"title":"To What Extent is Anfinsen's Thermodynamic Hypothesis Consistent With the Formation and Polymorphism of Amyloid Fibrils?","authors":"Yi Xiao Jiang, David S Eisenberg","doi":"10.1016/j.jmb.2025.169364","DOIUrl":"10.1016/j.jmb.2025.169364","url":null,"abstract":"<p><p>For half a century, Anfinsen's Thermodynamic Hypothesis has been considered the central pillar of protein science. In Anfinsen's words, this hypothesis holds that \"…the three-dimensional structure of a native protein in its normal physiological milieu…is the one in which the Gibbs free energy of the whole system is lowest; that is, that the native conformation is determined by the totality of interatomic interactions and hence by the amino acid sequence, in a given environment\". Applying this hypothesis to amyloid fibril-forming proteins presents challenges, which we contemplate in four questions. First, what is the \"native\" structure of amyloid-forming proteins, many of which are intrinsically disordered or are proteolytic fragments of larger proteins? Second, what is the thermodynamic landscape for the conversion of native monomers to highly stable fibril assemblies? Third, how do we reconcile Anfinsen's hypothesis, that a protein's amino acid sequence determines its 3-dimensional structure, with amyloid fibrils, for which single protein sequences are capable of folding into multiple polymorphs? Fourth, what is the \"physiological milieu\" of amyloid fibrils? Is it increased local concentration, cofactor binding, post-translational modifications, or cellular programming of diseased tissues? We discuss answers supplied by ex vivo observations and in vitro experiments, and conclude that amyloid protein structure in vivo is determined by its sequence and its physiological milieu.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169364"},"PeriodicalIF":4.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764332","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 miRNA–disease Association Prediction Via Residual GraphSAGE With Nonlinear Adaptive Feature Fusion and Triplet Contrastive Learning 基于非线性自适应特征融合和三联体对比学习的残差GraphSAGE人类mirna -疾病关联预测。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-07-28 DOI: 10.1016/j.jmb.2025.169360

Jianan Sui , Weirong Cui , Xiaoxiao Zhang , Hongliang Duan , Jingjing Guo

{"title":"Human miRNA–disease Association Prediction Via Residual GraphSAGE With Nonlinear Adaptive Feature Fusion and Triplet Contrastive Learning","authors":"Jianan Sui , Weirong Cui , Xiaoxiao Zhang , Hongliang Duan , Jingjing Guo","doi":"10.1016/j.jmb.2025.169360","DOIUrl":"10.1016/j.jmb.2025.169360","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) play pivotal roles in cellular regulation, and their dysregulation is closely linked to a wide spectrum of human diseases; thus, accurate miRNA–disease association prediction is critical for guiding experimental validation and therapeutic development. In this work, we propose RGFMDA, an innovative framework designed to predict miRNA-disease associations more effectively. RGFMDA employs a residual graph sampling and aggregation network to enhance information localization within miRNA and disease networks. It also features a nonlinear integration of features and a global context integration module that synergistically combine feature interactions and oversee global dependencies. Additionally, the framework uses triplet contrastive learning to refine the distinction between associated and non-associated miRNA-disease pairs, enhancing the accuracy of predictions. On the HMDD v2.0 benchmark, RGFMDA achieved an AUC of 0.9524, surpassing existing approaches whose reported AUC values range from approximately 0.916 to 0.942. On the HMDD v3.2 dataset, RGFMDA further improved performance with an AUC of 0.9604, exceeding state-of-the-art models that demonstrate AUCs between roughly 0.912 and 0.953. Case studies involving lung, esophageal, breast, and colorectal cancers have further confirmed the efficacy of RGFMDA. In summary, RGFMDA represents a robust and reliable computational tool for uncovering novel miRNA–disease associations, thereby facilitating future biological discovery and therapeutic development.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 19","pages":"Article 169360"},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751984","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 Long-Range Effects of Mutations: An Integrated Approach Using Elastic Network Models and Protein Structure Networks 破译突变的长期影响：使用弹性网络模型和蛋白质结构网络的综合方法。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-07-28 DOI: 10.1016/j.jmb.2025.169359

Karolina Krzesińska , Kristine Degn , Alicia Llorente , Eirini Giannakopoulou , Matteo Tiberti , Elena Papaleo

{"title":"Deciphering Long-Range Effects of Mutations: An Integrated Approach Using Elastic Network Models and Protein Structure Networks","authors":"Karolina Krzesińska , Kristine Degn , Alicia Llorente , Eirini Giannakopoulou , Matteo Tiberti , Elena Papaleo","doi":"10.1016/j.jmb.2025.169359","DOIUrl":"10.1016/j.jmb.2025.169359","url":null,"abstract":"<div><div>Understanding the impact of genetic variants on protein structure and function is essential for deciphering disease mechanisms. The MAVISp framework offers a systematic approach for evaluating structural effects, including variants with long-range impact. In this study, we critically evaluate and refine the LONG_RANGE module of MAVISp, leveraging data from over 400 proteins to optimize parameters for detecting significant response sites. We implement a systematic filtering workflow integrating allosteric free energy, distance constraints, solvent accessibility, and pocket localization to prioritize biologically relevant variants. We benchmarked the results against experimental data from deep mutational scans to identify the optimal combination of thresholds and filtering steps for assessing the impact of allosteric variants at response sites. Our analysis reveals that a 5.5 Å distance threshold, based on atomic distances, effectively minimizes the occurrence of local contacts in the allosteric map while preserving long-range effects. To address the limitations of the elastic network model for predicting allosteric free energy changes in non-globular proteins, we propose introducing three different metrics to assess protein globularity within the MAVISp framework, thereby supporting the design of the trimming to be applied to the input structure. Furthermore, we illustrate the potential of incorporating molecular dynamics simulations and algorithms for path analysis to confirm pairs of allosteric mutation sites and response sites involved in distal communication. Overall, we established a robust and scalable workflow for detecting allosteric protein variants, offering insights into structural communication and disease-associated protein variants.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 20","pages":"Article 169359"},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751983","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