Journal of Molecular Biology最新文献_第8页

Computational Analysis of the Accumulation of Mutations in Therapeutically Important RNA Viral Proteins During Pandemics with Special Emphasis on SARS-CoV-2 对流行病期间具有重要治疗作用的 RNA 病毒蛋白质突变积累的计算分析，特别强调 SARS-CoV-2 病毒。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-22 DOI: 10.1016/j.jmb.2024.168716

{"title":"Computational Analysis of the Accumulation of Mutations in Therapeutically Important RNA Viral Proteins During Pandemics with Special Emphasis on SARS-CoV-2","authors":"","doi":"10.1016/j.jmb.2024.168716","DOIUrl":"10.1016/j.jmb.2024.168716","url":null,"abstract":"<div><p>Single stranded RNA viruses are primary causative agents for pandemics, causing extensive morbidity and mortality worldwide. A pivotal question in pandemic preparedness and therapeutic intervention is what are the specific mutations which are more likely to emerge during such global health crises? This study aims to identify markers for mutations with the highest probability of emergence in these pandemics, focusing on the SARS-CoV-2 spike protein, an essential and therapeutically significant viral protein, starting from sequence information from the onset of the pandemic until July 2022. Quite consistently, we observed that emerged mutations tended to demonstrate a high genetic score, which reflects high similarity of the type of codon required for translation between an amino acid and to the mutated one. Further, this pattern is also observed in therapeutically significant proteins of other ssRNA pandemic viruses, including influenza (HA, NA), spike proteins of Ebola, envelope of Dengue and Chikungunya. We propose that the genetic score serves as an initial indicator, preceding the actual impact of the mutation on viral fitness. Finally, we developed a comprehensive computational pipeline to further explore and predict the subsequent effects of mutations on viral fitness. We believe that our pipeline can narrow down and predict future mutations in therapeutically important viral proteins during a pandemic.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003255/pdfft?md5=bf63ab1c81eeb4e9477ffc9040a5543a&pid=1-s2.0-S0022283624003255-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756376","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

ZC3H4/Restrictor Exerts a Stranglehold on Pervasive Transcription. ZC3H4/Restrictor 对普遍转录施加了限制。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-22 DOI: 10.1016/j.jmb.2024.168707

Chris Estell, Steven West

引用次数: 0

Everything AlphaFold tells us about protein knots AlphaFold 告诉我们关于蛋白质结的一切。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-17 DOI: 10.1016/j.jmb.2024.168715

{"title":"Everything AlphaFold tells us about protein knots","authors":"","doi":"10.1016/j.jmb.2024.168715","DOIUrl":"10.1016/j.jmb.2024.168715","url":null,"abstract":"<div><p>Recent advances in Machine Learning methods in structural biology opened up new perspectives for protein analysis. Utilizing these methods allows us to go beyond the limitations of empirical research, and take advantage of the vast amount of generated data. We use a complete set of potentially knotted protein models identified in all high-quality predictions from the AlphaFold Database to search for any common trends that describe them. We show that the vast majority of knotted proteins have 3<sub>1</sub> knot and that the presence of knots is preferred in neither Bacteria, Eukaryota, or Archaea domains. On the contrary, the percentage of knotted proteins in any given proteome is around 0.4%, regardless of the taxonomical group. We also verified that the organism’s living conditions do not impact the number of knotted proteins in its proteome, as previously expected. We did not encounter an organism without a single knotted protein. What is more, we found four universally present families of knotted proteins in Bacteria, consisting of SAM synthase, and TrmD, TrmH, and RsmE methyltransferases.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003243/pdfft?md5=0540f2834ee71fbcf6cb2dfe0a6a7aa8&pid=1-s2.0-S0022283624003243-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726623","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

Structure of the Bacteriophage PhiKZ Non-virion RNA Polymerase Transcribing from its Promoter p119L 噬菌体 PhiKZ 非病毒 RNA 聚合酶从其启动子 p119L 转录的结构。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-17 DOI: 10.1016/j.jmb.2024.168713

{"title":"Structure of the Bacteriophage PhiKZ Non-virion RNA Polymerase Transcribing from its Promoter p119L","authors":"","doi":"10.1016/j.jmb.2024.168713","DOIUrl":"10.1016/j.jmb.2024.168713","url":null,"abstract":"<div><p>Bacteriophage ΦKZ (PhiKZ) is the founding member of a family of giant bacterial viruses. It has potential as a therapeutic as its host, <em>Pseudomonas aeruginosa</em>, kills tens of thousands of people worldwide each year. ΦKZ infection is independent of the host transcriptional apparatus; the virus forms a “nucleus”, producing a proteinaceous barrier around the ΦKZ genome that excludes the host immune systems. It expresses its own non-canonical multi-subunit non-virion RNA polymerase (nvRNAP), which is imported into its “nucleus” to transcribe viral genes. The ΦKZ nvRNAP is formed by four polypeptides representing homologues of the eubacterial β/β′ subunits, and a fifth that is likely to have evolved from an ancestral homologue to σ-factor. We have resolved the structure of the ΦKZ nvRNAP initiating transcription from its cognate promoter, p119L, including previously disordered regions. Our results shed light on the similarities and differences between ΦKZ nvRNAP mechanisms of transcription and those of canonical eubacterial RNAPs and the related non-canonical nvRNAP of bacteriophage AR9.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002228362400322X/pdfft?md5=124d118c21dd6c1283bbfa345e8f262b&pid=1-s2.0-S002228362400322X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726625","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

igRNA Prediction and Selection AI Models (igRNA-PS) for Bystander-less ABE Base Editing 用于无旁观者 ABE 碱基编辑的 igRNA 预测和选择 AI 模型 (igRNA-PS)。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-17 DOI: 10.1016/j.jmb.2024.168714

{"title":"igRNA Prediction and Selection AI Models (igRNA-PS) for Bystander-less ABE Base Editing","authors":"","doi":"10.1016/j.jmb.2024.168714","DOIUrl":"10.1016/j.jmb.2024.168714","url":null,"abstract":"<div><p>CRISPR derived base editing techniques tend to edit multiple bases in the targeted region, which impedes precise reversion of disease-associated single nucleotide variations (SNVs). We designed an imperfect gRNA (igRNA) editing strategy to achieve bystander-less single-base editing. To predict the performance and provide ready-to-use igRNAs, we employed a high-throughput method to edit 5000 loci, each with approximate 19 systematically designed ABE igRNAs. Through deep learning of the relationship of editing efficiency, original gRNA sequence and igRNA sequence, AI models were constructed and tested, designated igRNA Prediction and Selection AI models (igRNA-PS). The models have three functions, First, they can identify the major editing site from the bystanders on a gRNA protospacer with a near 90% accuracy. second, a modified single-base editing efficiency (SBE), considering both single-base editing efficiency and product purity, can be predicted for any given igRNAs. Third, for an editing locus, a set of 64 igRNAs derived from a gRNA can be generated, evaluated through igRNA-PS to select for the best performer, and provided to the user. In this work, we overcome one of the most significant obstacles of base editors, and provide a convenient and efficient approach for single-base bystander-less ABE base editing.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726624","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

CRTAC1 has a Compact β-propeller–TTR Core Stabilized by Potassium Ions CRTAC1 有一个由钾离子稳定的紧凑型β-推进器-TTR 核心。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-17 DOI: 10.1016/j.jmb.2024.168712

{"title":"CRTAC1 has a Compact β-propeller–TTR Core Stabilized by Potassium Ions","authors":"","doi":"10.1016/j.jmb.2024.168712","DOIUrl":"10.1016/j.jmb.2024.168712","url":null,"abstract":"<div><p>Cartilage acidic protein-1 (CRTAC1) is a secreted glycoprotein with roles in development, function and repair of the nervous system. It is linked to ischemic stroke, osteoarthritis and (long) COVID outcomes, and has suppressive activity in carcinoma and bladder cancer. Structural characterization of CRTAC1 has been complicated by its tendency to form disulfide-linked aggregates. Here, we show that CRTAC1 is stabilized by potassium ions. Using x-ray crystallography, we determined the structure of CRTAC1 to 1.6 Å. This reveals that the protein consists of a three-domain fold, including a previously-unreported compact β-propeller–TTR combination, in which an extended loop of the TTR plugs the β-propeller core. Electron density is observed for ten bound ions: six calcium, three potassium and one sodium. Low potassium ion concentrations lead to changes in tryptophan environment and exposure of two buried free cysteines located on a β-blade and in the β-propeller-plugging TTR loop. Mutating the two free cysteines to serines prevents covalent intermolecular interactions, but not aggregation, in absence of potassium ions. The potassium ion binding sites are located between the blades of the β-propeller, explaining their importance for the stability of the CRTAC1 fold. Despite varying in sequence, the three potassium ion binding sites are structurally similar and conserved features of the CRTAC protein family. These insights into the stability and structure of CRTAC1 provide a basis for further work into the function of CRTAC1 in health and disease.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003218/pdfft?md5=f7d76bbbcb87f758d8e22a4764cd5bf7&pid=1-s2.0-S0022283624003218-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726622","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

RNase R Affects the Level of Fatty Acid Biosynthesis Transcripts Leading to Changes in membrane Fluidity RNase R 影响脂肪酸合成转录本的水平，导致膜流动性发生变化。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-15 DOI: 10.1016/j.jmb.2024.168711

{"title":"RNase R Affects the Level of Fatty Acid Biosynthesis Transcripts Leading to Changes in membrane Fluidity","authors":"","doi":"10.1016/j.jmb.2024.168711","DOIUrl":"10.1016/j.jmb.2024.168711","url":null,"abstract":"<div><p>Previous studies on RNase R have highlighted significant effects of this ribonuclease in several processes of <em>Streptococcus pneumoniae</em> biology. In this work we show that elimination of RNase R results in overexpression of most of genes encoding the components of type II fatty acid biosynthesis (FASII) cluster. We demonstrate that RNase R is implicated in the turnover of most of transcripts from this pathway, affecting the outcome of the whole FASII cluster, and ultimately leading to changes in the membrane fatty acid composition. Our results show that the membrane of the deleted strain contains higher proportion of unsaturated and long-chained fatty acids than the membrane of the wild type strain. These alterations render the RNase R mutant more prone to membrane lipid peroxidation and are likely the reason for the increased sensitivity of this strain to detergent lysis and to the action of the bacteriocin nisin.</p><p>Reprogramming of membrane fluidity is an adaptative cell response crucial for bacterial survival in constantly changing environmental conditions. The data presented here is suggestive of a role for RNase R in the composition of <em>S. pneumoniae</em> membrane, with strong impact on pneumococci adaptation to different stress situations.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003206/pdfft?md5=dbb516a26036ed8ffa9450e7aed04165&pid=1-s2.0-S0022283624003206-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632222","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

Structural Basis of Nucleotide Selectivity in Pyruvate Kinase 丙酮酸激酶核苷酸选择性的结构基础

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-14 DOI: 10.1016/j.jmb.2024.168708

{"title":"Structural Basis of Nucleotide Selectivity in Pyruvate Kinase","authors":"","doi":"10.1016/j.jmb.2024.168708","DOIUrl":"10.1016/j.jmb.2024.168708","url":null,"abstract":"<div><p>Nucleoside triphosphates are indispensable in numerous biological processes, with enzymes involved in their biogenesis playing pivotal roles in cell proliferation. Pyruvate kinase (PYK), commonly regarded as the terminal glycolytic enzyme that generates ATP in tandem with pyruvate, is also capable of synthesizing a wide range of nucleoside triphosphates from their diphosphate precursors. Despite their substrate promiscuity, some PYKs show preference towards specific nucleotides, suggesting an underlying mechanism for differentiating nucleotide bases. However, the thorough characterization of this mechanism has been hindered by the paucity of nucleotide-bound PYK structures. Here, we present crystal structures of <em>Streptococcus pneumoniae</em> PYK in complex with four different nucleotides. These structures facilitate direct comparison of the protein-nucleotide interactions and offer structural insights into its pronounced selectivity for GTP synthesis. Notably, this selectivity is dependent on a sequence motif in the nucleotide recognition site that is widely present among prokaryotic PYKs, particularly in Firmicutes species. We show that pneumococcal cell growth is significantly impaired when expressing a PYK variant with compromised GTP and UTP synthesis activity, underscoring the importance of PYK in maintaining nucleotide homeostasis. Our findings collectively advance our understanding of PYK biochemistry and prokaryotic metabolism.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624003176/pdfft?md5=d56aaf95882d9d000dd3457b43831f69&pid=1-s2.0-S0022283624003176-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618901","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

Molecular Crosstalk Between Adherens Junction Proteins, E-cadherin and Nectin-4 粘连连接蛋白、E-cadherin 和 nectin-4 之间的分子串扰。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-14 DOI: 10.1016/j.jmb.2024.168709

{"title":"Molecular Crosstalk Between Adherens Junction Proteins, E-cadherin and Nectin-4","authors":"","doi":"10.1016/j.jmb.2024.168709","DOIUrl":"10.1016/j.jmb.2024.168709","url":null,"abstract":"<div><p>Cell-cell junctions formed by the association of cell adhesion molecules facilitate physiological events necessary for growth and development of multicellular organisms. Among them, cadherins and nectins organize and assemble to form adherens junction, which thereby mechanically couples interacting cells. A detailed understanding of the crosstalk involving these cell adhesion molecules is fundamental to the study of the various developmental processes. Although, cadherins and nectins can recruit each other in the adherens junction through an interplay of cytoplasmic adaptor molecules, here, we report a direct interaction between N-terminal extracellular domains of E-cadherin and nectin-4 as demonstrated by surface plasmon resonance (SPR) and Atomic Force Microscopy (AFM)-based single molecule force spectroscopy (SMFS). Kinetic studies using SPR demonstrate the binding between the ectodomains of E-cadherin and nectin-4 with a K<sub>D</sub> of 3.7 ± 0.7 µM and K<sub>D</sub> of 5.4 ± 0.2 µM (reciprocal experiment). AFM-based SMFS experiments also support interaction between the ectodomains of E-cadherin and nectin-4 with the <em>k</em><sub>off</sub> value of 31.48 ± 1.53 s<sup>−1</sup> and the lifetime of the complex of 0.036 ± 0.0026 s. We thus propose a cell adhesion mechanism mediated by E-cadherin and nectin-4, which can have functional significance in early embryogenesis as evident from the expression pattern of both the proteins during early development.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618900","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

Rational Tuning of the Concentration-independent Enrichment of Prion-like Domains in Stress Granules 合理调整应激颗粒中与浓度无关的朊病毒样结构域的富集。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2024-07-14 DOI: 10.1016/j.jmb.2024.168703

{"title":"Rational Tuning of the Concentration-independent Enrichment of Prion-like Domains in Stress Granules","authors":"","doi":"10.1016/j.jmb.2024.168703","DOIUrl":"10.1016/j.jmb.2024.168703","url":null,"abstract":"<div><p>Stress granules (SGs) are large ribonucleoprotein assemblies that form in response to acute stress in eukaryotes. SG formation is thought to be initiated by liquid–liquid phase separation (LLPS) of key proteins and RNA. These molecules serve as a scaffold for recruitment of client molecules. LLPS of scaffold proteins <em>in vitro</em> is highly concentration-dependent, yet biomolecular condensates <em>in vivo</em> contain hundreds of unique proteins, most of which are thought to be clients rather than scaffolds. Many proteins that localize to SGs contain low-complexity, prion-like domains (PrLDs) that have been implicated in LLPS and SG recruitment. The degree of enrichment of proteins in biomolecular condensates such as SGs can vary widely, but the underlying basis for these differences is not fully understood. Here, we develop a toolkit of model PrLDs to examine the factors that govern efficiency of PrLD recruitment to stress granules. Recruitment was highly sensitive to amino acid composition: enrichment in SGs could be tuned through subtle changes in hydrophobicity. By contrast, SG recruitment was largely insensitive to PrLD concentration at both a population level and single-cell level. These observations point to a model wherein PrLDs are enriched in SGs through either simple solvation effects or interactions that are effectively non-saturable even at high expression levels.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615581","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