Journal of Molecular Biology最新文献_第7页

The Host miR-17-92 Cluster Negatively Regulates Mouse Mammary Tumor Virus (MMTV) Replication Primarily Via Cluster Member miR-92a 宿主 miR-17-92 簇主要通过簇成员 miR-92a 负向调控小鼠乳腺肿瘤病毒 (MMTV) 复制。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-08-06 DOI: 10.1016/j.jmb.2024.168738

{"title":"The Host miR-17-92 Cluster Negatively Regulates Mouse Mammary Tumor Virus (MMTV) Replication Primarily Via Cluster Member miR-92a","authors":"","doi":"10.1016/j.jmb.2024.168738","DOIUrl":"10.1016/j.jmb.2024.168738","url":null,"abstract":"<div><p>The mouse mammary tumor virus (MMTV) is a well-known causative agent of breast cancer in mice. Previously, we have shown that MMTV dysregulates expression of the host miR-17-92 cluster in MMTV-infected mammary glands and MMTV-induced tumors. This cluster, better known as oncomiR-1, is frequently dysregulated in cancers, particularly breast cancer. In this study, our aim was to uncover a functional interaction between MMTV and the cluster. Our results reveal that MMTV expression led to dysregulation of the cluster in both mammary epithelial HC11 and HEK293T cells with the expression of miR-92a cluster member being affected the most. Conversely, overexpression of the whole or partial cluster significantly repressed MMTV expression. Notably, overexpression of cluster member miR-92a alone repressed MMTV expression to the same extent as overexpression of the complete/partial cluster. Inhibition of miR-92a led to nearly a complete restoration of MMTV expression, while deletion/substitution of the miR-92a seed sequence rescued MMTV expression. Dual luciferase assays identified MMTV genomic RNA as the potential target of miR-92a. These results show that the miR-17-92 cluster acts as part of the cell’s well-known miRNA-based anti-viral response to thwart incoming MMTV infection. Thus, this study provides the first evidence highlighting the biological significance of host miRNAs in regulating MMTV replication and potentially influencing tumorigenesis.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003474/pdfft?md5=04a973754bd47af28d9638641141dae1&pid=1-s2.0-S0022283624003474-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Slow Misfolding of a Molten Globule form of a Mutant Prion Protein Variant into a β-rich Dimer 突变朊病毒蛋白变体的熔融球形缓慢错误折叠成富含β的二聚体。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-08-05 DOI: 10.1016/j.jmb.2024.168736

{"title":"Slow Misfolding of a Molten Globule form of a Mutant Prion Protein Variant into a β-rich Dimer","authors":"","doi":"10.1016/j.jmb.2024.168736","DOIUrl":"10.1016/j.jmb.2024.168736","url":null,"abstract":"<div><p>Misfolding of the prion protein is linked to multiple neurodegenerative diseases. A better understanding of the process requires the identification and structural characterization of intermediate conformations <em>via</em> which misfolding proceeds. In this study, three conserved aromatic residues (Tyr168, Phe174, and Tyr217) located in the C-terminal domain of mouse PrP (wt moPrP) were mutated to Ala. The resultant mutant protein, 3A moPrP, is shown to adopt a molten globule (MG)-like native conformation. Hydrogen-deuterium exchange studies coupled with mass spectrometry revealed that for 3A moPrP, the free energy gap between the MG-like native conformation and misfolding-prone partially unfolded forms is reduced. Consequently, 3A moPrP misfolds in native conditions even in the absence of salt, unlike wt moPrP, which requires the addition of salt to misfold. 3A moPrP misfolds to a β-rich dimer in the absence of salt, which can rapidly form an oligomer upon the addition of salt. In the presence of salt, 3A moPrP misfolds to a β-rich oligomer about a thousand-fold faster than wt moPrP. Importantly, the misfolded structure of the dimer is similar to that of the salt-induced oligomer. Misfolding to oligomer seems to be induced at the level of the dimeric unit by monomer–monomer association, and the oligomer grows by accretion of misfolded dimeric units. Additionally, it is shown that the conserved aromatic residues collectively stabilize not only monomeric protein, but also the structural core of the β-rich oligomers. Finally, it is also shown that 3A moPrP misfolds much faster to amyloid-fibrils than does the wt protein.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888033","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

Effectiveness and Efficiency: Label-Aware Hierarchical Subgraph Learning for Protein-Protein Interaction. 效果与效率：针对蛋白质-蛋白质相互作用的标签感知分层子图学习。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-08-03 DOI: 10.1016/j.jmb.2024.168737

Yuanqing Zhou, Haitao Lin, Lianghua Xie, Yufei Huang, Lirong Wu, Stan Z Li, Wei Chen

{"title":"Effectiveness and Efficiency: Label-Aware Hierarchical Subgraph Learning for Protein-Protein Interaction.","authors":"Yuanqing Zhou, Haitao Lin, Lianghua Xie, Yufei Huang, Lirong Wu, Stan Z Li, Wei Chen","doi":"10.1016/j.jmb.2024.168737","DOIUrl":"10.1016/j.jmb.2024.168737","url":null,"abstract":"<p><p>The study of protein-protein interactions (PPIs) holds immense significance in understanding various biological activities, as well as in drug discovery and disease diagnosis. Existing deep learning methods for PPI prediction, including graph neural networks (GNNs), have been widely employed as the solutions, while they often experience a decline in performance in the real world. We claim that the topological shortcut is one of the key problems contributing negatively to the performance, according to our analysis. By modeling the PPIs as a graph with protein as nodes and interactions as edge types, the prevailing models tend to learn the pattern of nodes' degrees rather than intrinsic sequence-structure profiles, leading to the problem termed topological shortcut. The huge data growth of PPI leads to intensive computational costs and challenges computing devices, causing infeasibility in practice. To address the discussed problems, we propose a label-aware hierarchical subgraph learning method (laruGL-PPI) that can effectively infer PPIs while being interpretable. Specifically, we introduced edge-based subgraph sampling to effectively alleviate the problems of topological shortcuts and high computing costs. Besides, the inner-outer connections of PPIs are modeled as a hierarchical graph, together with the dependencies between interaction types constructed by a label graph. Extensive experiments conducted across various scales of PPI datasets have conclusively demonstrated that the laruGL-PPI method surpasses the most advanced PPI prediction techniques currently available, particularly in the testing of unseen proteins. Also, our model can recognize crucial sites of proteins, such as surface sites for binding and active sites for catalysis.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892549","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 Phosphatase RosC from Streptomyces davaonensis is Used for Roseoflavin Biosynthesis and has Evolved to Largely Prevent Dephosphorylation of the Important Cofactor Riboflavin-5′-phosphate 来自达瓦昂链霉菌（Streptomyces davaonensis）的磷酸酶 RosC 用于玫瑰黄素的生物合成，其进化在很大程度上防止了重要辅助因子核黄素-5'-磷酸的去磷酸化。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-08-02 DOI: 10.1016/j.jmb.2024.168734

{"title":"The Phosphatase RosC from Streptomyces davaonensis is Used for Roseoflavin Biosynthesis and has Evolved to Largely Prevent Dephosphorylation of the Important Cofactor Riboflavin-5′-phosphate","authors":"","doi":"10.1016/j.jmb.2024.168734","DOIUrl":"10.1016/j.jmb.2024.168734","url":null,"abstract":"<div><p>The antibiotic roseoflavin is a riboflavin (vitamin B<sub>2</sub>) analog. One step of the roseoflavin biosynthetic pathway is catalyzed by the phosphatase RosC, which dephosphorylates 8-demethyl-8-amino-riboflavin-5′-phosphate (AFP) to 8-demethyl-8-amino-riboflavin (AF). RosC also catalyzes the potentially cell-damaging dephosphorylation of the AFP analog riboflavin-5′-phosphate also called “flavin mononucleotide” (FMN), however, with a lower efficiency. We performed X-ray structural analyses and mutagenesis studies on RosC from <em>Streptomyces davaonensis</em> to understand binding of the flavin substrates, the distinction between AFP and FMN and the catalytic mechanism of this enzyme. This work is the first structural analysis of an AFP phosphatase. Each monomer of the RosC dimer consists of an α/β-fold core, which is extended by three specific elongated strand-to-helix sections and a specific N-terminal helix. Altogether these segments envelope the flavin thereby forming a novel flavin-binding site. We propose that distinction between AFP and FMN is provided by substrate-induced rigidification of the four RosC specific supplementary segments mentioned above and by an interaction between the amino group at C8 of AFP and the β-carboxylate of D166. This key amino acid is involved in binding the ring system of AFP and positioning its ribitol phosphate part. Accordingly, site-specific exchanges at D166 disturbed the active site geometry of the enzyme and drastically reduced the catalytic activity. Based on the structure of the catalytic core we constructed a whole series of RosC variants but a disturbing, FMN dephosphorylating “killer enzyme”, was not generated.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003437/pdfft?md5=1dfc21c08fea5edd24e540b6af1dcffe&pid=1-s2.0-S0022283624003437-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanisms of RNA Polymerase II Termination at the 3'-End of Genes. RNA 聚合酶 II 在基因 3'- 端终止的机制。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-08-02 DOI: 10.1016/j.jmb.2024.168735

David Lopez Martinez, Jesper Q Svejstrup

{"title":"Mechanisms of RNA Polymerase II Termination at the 3'-End of Genes.","authors":"David Lopez Martinez, Jesper Q Svejstrup","doi":"10.1016/j.jmb.2024.168735","DOIUrl":"10.1016/j.jmb.2024.168735","url":null,"abstract":"<p><p>RNA polymerase II (RNAPII) is responsible for the synthesis of a diverse set of RNA molecules, including protein-coding messenger RNAs (mRNAs) and many short non-coding RNAs (ncRNAs). For this purpose, RNAPII relies on a multitude of factors that regulate the transcription cycle, from initiation and promoter-proximal pausing, through elongation and finally termination. RNAPII transcription termination at the end of genes ensures the release of RNAPII from the DNA template and its efficient recycling for further rounds of transcription. Termination of RNAPII is tightly coupled to 3'-end mRNA processing, which constitutes an important trigger for the subsequent transcription termination event. In this review, we discuss the current understanding of RNAPII termination mechanisms, focusing on 'canonical' termination at the 3'-end of genes. We also integrate the allosteric and 'torpedo' models into a unified model of termination, and describe the different termination factors that have been identified to date, paying special attention to the human factors and their mechanism of action at the molecular level. Indeed, in recent years the development of novel approaches in structural biology, biochemistry and cell biology have together led to a more detailed comprehension of the different mechanisms of RNAPII termination, and a better understanding of their importance in regulating gene expression, especially under cellular stress and pathological situations.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888032","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

Per Os to Protection – Targeting the Oral Route to Enhance Immune-mediated Protection from Disease of the Human Newborn 从口腔到保护--通过口腔途径加强对新生儿疾病的免疫保护。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-31 DOI: 10.1016/j.jmb.2024.168718

引用次数: 0

Tuning the Functionality of Designer Translating Organelles with Orthogonal tRNA Synthetase/tRNA Pairs. 用正交 tRNA 合成酶/tRNA 对调整设计翻译细胞器的功能。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-30 DOI: 10.1016/j.jmb.2024.168728

Mikhail E Sushkin, Marius Jung, Edward A Lemke

{"title":"Tuning the Functionality of Designer Translating Organelles with Orthogonal tRNA Synthetase/tRNA Pairs.","authors":"Mikhail E Sushkin, Marius Jung, Edward A Lemke","doi":"10.1016/j.jmb.2024.168728","DOIUrl":"10.1016/j.jmb.2024.168728","url":null,"abstract":"<p><p>Site-specific incorporation of noncanonical amino acids (ncAAs) can be realized by genetic code expansion (GCE) technology. Different orthogonal tRNA synthetase/tRNA (RS/tRNA) pairs have been developed to introduce a ncAA at the desired site, delivering a wide variety of functionalities that can be installed into selected proteins. Cytoplasmic expression of RS/tRNA pairs can cause a problem with background ncAA incorporation into host proteins. The application of orthogonally translating organelles (OTOs), inspired by the concept of phase separation, provides a solution for this issue in mammalian cells, allowing site-specific and protein-selective ncAA incorporation. So far, only Methanosarcina mazei (Mm) pyrrolysyl-tRNA synthetase (PylRS) has been used within OTOs, limiting the method's potential. Here, we explored the implementation of four other widely used orthogonal RS/tRNA pairs with OTOs, which, to our surprise, were unsuccessful in generating mRNA-selective GCE. Next, we tested several experimental solutions and developed a new chimeric phenylalanyl-RS/tRNA pair that enables ncAA incorporation in OTOs in a site-specific and protein-selective manner. Our work reveals unaccounted design constraints in the spatial engineering of enzyme functions using designer organelles and presents a strategy to overcome those in vivo. We then discuss current limitations and future directions of in-cell engineering in general and protein engineering using GCE specifically.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873832","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

Caprin1 Bridges PRMT1 to G3BP1 and Spaces Them to Ensure Proper Stress Granule Formation Caprin1 将 PRMT1 与 G3BP1 连接起来，并将它们分开，以确保应力颗粒的正常形成

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-28 DOI: 10.1016/j.jmb.2024.168727

引用次数: 0

Reconstituted Cell-free Translation Systems for Exploring Protein Folding and Aggregation 用于探索蛋白质折叠和聚集的重组无细胞翻译系统。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-27 DOI: 10.1016/j.jmb.2024.168726

引用次数: 0

AAontology: An Ontology of Amino Acid Scales for Interpretable Machine Learning AAontology：用于可解释机器学习的氨基酸尺度本体。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-24 DOI: 10.1016/j.jmb.2024.168717

{"title":"AAontology: An Ontology of Amino Acid Scales for Interpretable Machine Learning","authors":"","doi":"10.1016/j.jmb.2024.168717","DOIUrl":"10.1016/j.jmb.2024.168717","url":null,"abstract":"<div><p>Amino acid scales are crucial for protein prediction tasks, many of them being curated in the AAindex database. Despite various clustering attempts to organize them and to better understand their relationships, these approaches lack the fine-grained classification necessary for satisfactory interpretability in many protein prediction problems.</p><p>To address this issue, we developed AAontology—a two-level classification for 586 amino acid scales (mainly from AAindex) together with an in-depth analysis of their relations—using bag-of-word-based classification, clustering, and manual refinement over multiple iterations. AAontology organizes physicochemical scales into 8 categories and 67 subcategories, enhancing the interpretability of scale-based machine learning methods in protein bioinformatics. Thereby it enables researchers to gain a deeper biological insight. We anticipate that AAontology will be a building block to link amino acid properties with protein function and dysfunctions as well as aid informed decision-making in mutation analysis or protein drug design.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003267/pdfft?md5=2d1d4fa424ae4f73bf95e3ab666e7883&pid=1-s2.0-S0022283624003267-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0