Journal of Molecular Biology最新文献_第2页

Rising Stars: Bioinformatics of post-translational modifications. 冉冉升起的新星：翻译后修饰的生物信息学。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-07 DOI: 10.1016/j.jmb.2025.169478

Yu Xue

{"title":"Rising Stars: Bioinformatics of post-translational modifications.","authors":"Yu Xue","doi":"10.1016/j.jmb.2025.169478","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169478","url":null,"abstract":"Yu Xue is a professor in the College of Life Science and Technology at Huazhong University of Science and Technology, and hold a joint position in the Hubei Hongshan Laboratory at Huazhong Agricultural University. He received two B.E. degrees in polymer science and technology and computer science from the University of Science and Technology of China (USTC) in 2002, and a Ph.D. degree in cell biology from USTC in 2006. His major research interest is the computational analysis of post-translational modifications (PTMs) in proteins, a field he terms PTM bioinformatics. Since 2004, his group has developed a number of algorithms, including the Group-based Prediction System (GPS), for prediction of PTM sites and their functional relevance. They have also constructed several PTM-related databases and designed methods to analyze PTMomic data and infer key regulatory enzymes. Through extensive collaboration and their own experimental work, they have predicted and uncovered new PTM sites and regulators in dynamic biological processes. He served as a co-founder and secretary general of the Artificial Intelligence Biology (AIBIO) Sub-branch of the Biophysical Society of China. In 2023, he proposed the concept of \"vit-molecular language\", drawing an analogy between PTM regulation and human natural languages. He anticipates that cutting-edge AI technology, combined with conventional bioinformatics and experimental approaches, will profoundly empower future PTM studies.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169478"},"PeriodicalIF":4.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257058","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

Connecting In Vitro and In Vivo Studies of Biomolecular Interaction and Assembly. 编辑：连接生物分子相互作用和组装的体外和体内研究。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-06 DOI: 10.1016/j.jmb.2025.169479

William M Gelbart, George P Lomonossoff

引用次数: 0

Unveiling Eukaryotic Membrane Proteins in High Resolution Using Peptide Solubilization 利用肽增溶技术高分辨率揭示真核膜蛋白。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-06 DOI: 10.1016/j.jmb.2025.169467

Jiahe Zang , Yiting Shi , Weiyu Tao , Xiaoyu Liu , Wenjun Guo , Lei Chen

引用次数: 0

Stability and adaptation of proteins, membranes and cells to extreme temperature and pressure. 蛋白质、膜和细胞对极端温度和压力的稳定性和适应性。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-06 DOI: 10.1016/j.jmb.2025.169477

J Peters, J G LoRicco, M Saracco, A Caliò, P Oger

引用次数: 0

Addressing structural heterogeneity in real-time tracking of protein dynamics triggered by caged compounds. 笼化化合物引发的蛋白质动态实时跟踪中的结构异质性。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-06 DOI: 10.1016/j.jmb.2025.169476

Konstantinos Magkakis, Fredrik Orädd, Christian Pett, Marie Lycksell, Kevin Pounot, Matteo Levantino, Magnus Andersson

{"title":"Addressing structural heterogeneity in real-time tracking of protein dynamics triggered by caged compounds.","authors":"Konstantinos Magkakis, Fredrik Orädd, Christian Pett, Marie Lycksell, Kevin Pounot, Matteo Levantino, Magnus Andersson","doi":"10.1016/j.jmb.2025.169476","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169476","url":null,"abstract":"Protein molecules typically carry out their biological function by adopting multiple, transient conformations, which complicates their structural characterization. Synchrotron-based time-resolved X-ray solution scattering (TR-XSS) combined with triggering by caged compounds enables real-time monitoring of protein structural transitions in a wide range of protein targets. However, non-instantaneous release of photosensitive cages and undefined equilibrium states complicate data interpretation. In this work, we addressed these challenges with the Escherichia coli adenylate kinase (AdK) enzyme as a model system. To account for, and visualize, heterogeneity resulting from overlap between the ATP release kinetics and protein catalytic motions, we based the structural refinement on ensembles from a pool of putative target structures generated by molecular dynamics (MD) simulations. Under equilibrium conditions, protein conformations preferentially occupied intermediate states in which the ATP- and AMP-binding domains were never fully opened or closed. Upon ATP availability, ensembles successively shifted toward fully closed and open conformations accompanying partial unfolding, which is consistent with a cracking model for triggering the enzymatic reaction. The findings demonstrate that non-instantaneous substrate release can significantly impact protein transition kinetics but can be tackled with the use of ensemble-based structural refinement. Hence, this work establishes a framework for dissecting rapid protein conformational changes in solution induced by caged compounds.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169476"},"PeriodicalIF":4.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249146","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

Early-stage determinants of T1-S1 conformations in Kv1.3 channels. Kv1.3通道T1-S1构象的早期决定因素。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-04 DOI: 10.1016/j.jmb.2025.169474

Liwei Tu, Aaron Sykes, Therese Davis, Sophia Gross, Carol Deutsch

{"title":"Early-stage determinants of T1-S1 conformations in Kv1.3 channels.","authors":"Liwei Tu, Aaron Sykes, Therese Davis, Sophia Gross, Carol Deutsch","doi":"10.1016/j.jmb.2025.169474","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169474","url":null,"abstract":"Early-stage biogenesis of voltage-gated potassium channels (Kv) remains remarkably understudied yet is key to defining co- and post-translational acquisition of Kv secondary, tertiary, and quaternary conformations. Thus, we have studied nascent folding events and their determinants in Kv1.3, a tetrameric ion channel highly expressed in nerve and immune cells. We explore how folding of the T1-S1 linker and T1, an intersubunit recognition domain that ensures correct isoform assembly, are modulated by molecular determinants in the Kv subunit. We focus on the highly conserved C-terminal sequence, S0, in the T1-S1 linker. Using pegylation, a mass-tagging strategy, inter- and intrasubunit crosslinking, we define the molecular determinants of T1-S1 linker accessibility and location. Our findings show that i) dynamic protein-lipid and protein-protein linker interfaces exist, ii) the presence of a T1 domain and its conformation (monomer versus tetramer) impact linker properties, iii) helical formation of S0 occurs in early biogenic stages and does not require the presence of membranes, iv) a core recognition domain (T2) increases T1 dimerization efficiency and promotes tetramer formation, and v) as few as 12 native linker residues enable T1 tetramerization. These findings differ from canonical models and suggest that domain plasticity for Kv1.3 contributes to biogenesis and may underlie domain-domain communication in Kv function.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169474"},"PeriodicalIF":4.5,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237898","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

Retroviral Vector Technology for Gene Therapy: History, Current Landscape, and Future Prospects. 逆转录病毒载体技术用于基因治疗：历史、现状和未来展望。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-03 DOI: 10.1016/j.jmb.2025.169473

Soumeya Ali Jaballah, Lizna M Ali, Mohammad Abdullah Jehad, Shaima Akhlaq, Tahir A Rizvi, Farah Mustafa

{"title":"Retroviral Vector Technology for Gene Therapy: History, Current Landscape, and Future Prospects.","authors":"Soumeya Ali Jaballah, Lizna M Ali, Mohammad Abdullah Jehad, Shaima Akhlaq, Tahir A Rizvi, Farah Mustafa","doi":"10.1016/j.jmb.2025.169473","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169473","url":null,"abstract":"The concept of gene therapy and its practice has been prevalent for over five decades. The first successful retroviral vector-based gene therapy trial took place ∼35 years ago, followed by several setbacks. However, recent years have seen a surge in successes, offering new hope to patients with genetic and other disorders once deemed untreatable. Over the past decade, rapid advancements in molecular biology have led to the development of safer and more effective gene therapy strategies with various gene delivery systems now in use. Among these, viral vectors such as retroviruses, adenoviruses, and adeno-associated viruses are the most widely employed in both research and clinical settings. This is due to their natural efficiency in delivering genetic material into target cells. Among these viral vectors, retroviruses stand out for their unique ability to reverse-transcribe and integrate their genetic material into the host genome, ensuring stable and long-term gene expression. This review highlights advances in retroviral vector development, examining both their therapeutic potential and associated challenges. It also explores strategies for vector production, including transient and stable systems tailored to meet clinical and regulatory demands. Significant progress is discussed in mitigating insertional mutagenesis and vector silencing. As a result, next-generation retroviral vectors with improved safety and efficacy have made it past regulatory-approval and are commercially available. Current innovations include replication-competent, non-integrating, integration-re-targeted, and hybrid CRISPR/Cas-expressing retroviral vectors undergoing pre-clinical and clinical investigations. This reflects a new era in gene therapy, with retroviral vectors reimagined for greater precision, control, and therapeutic impact.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169473"},"PeriodicalIF":4.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231061","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

Dimer Dissociation and Aggregation Hot-spot Exposure Synergistically Accelerate Light Chain Variable Domain Aggregation Associated With AL Amyloidosis. 二聚体解离和聚集热点暴露协同加速与AL淀粉样变性相关的轻链可变结构域聚集。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-10-01 DOI: 10.1016/j.jmb.2025.169468

Sarita Puri, Sharvari Palkar, Amit Kumawat, Ishaan Chaudhary, Basudha Patel, V Vinoth Kumar, Manoj K Sriramoju, Kanchan Garai, Shang-Te Danny Hsu, Stefano Ricagno

{"title":"Dimer Dissociation and Aggregation Hot-spot Exposure Synergistically Accelerate Light Chain Variable Domain Aggregation Associated With AL Amyloidosis.","authors":"Sarita Puri, Sharvari Palkar, Amit Kumawat, Ishaan Chaudhary, Basudha Patel, V Vinoth Kumar, Manoj K Sriramoju, Kanchan Garai, Shang-Te Danny Hsu, Stefano Ricagno","doi":"10.1016/j.jmb.2025.169468","DOIUrl":"10.1016/j.jmb.2025.169468","url":null,"abstract":"Light chain (AL) amyloidosis is a life-threatening systemic disorder caused by the aggregation and deposition of antibody light chain (LC) fragments in multiple organs, including the heart and kidneys. In this study, we investigated the early events of aggregation of the highly unstable variable domain (VL) from AL55, a known amyloidogenic and cardiotoxic light chain. Our results show that dimer disruption and exposure of aggregation hot spots synergistically accelerate aggregation. At neutral pH, concentration-dependent dimerization reduces aggregation by limiting aggregation-competent monomers. Dilution or lowering the pH disrupts dimerization, exposes aggregation-prone regions (APRs), and accelerates aggregation. In contrast, when APRs are chemically stabilized, the aggregation rate decreases despite high monomer availability. Together, this study establishes that AL55 VL domain aggregation is regulated by dimer dissociation, electrostatic modulation, and formation of an aggregation-competent conformation involving a dynamic N-terminal (residues 5-26) and dimeric interface (residues 38-56) region, ultimately yielding structurally compact and highly stable fibrils.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169468"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224613","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

Protein Kinase A Phosphorylates a Conformationally High-Energy State of Raf Kinase Inhibitory Protein. 蛋白激酶A磷酸化Raf激酶抑制蛋白的构象高能态。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-09-26 DOI: 10.1016/j.jmb.2025.169466

Cristina Olivieri, Carmen Biancaniello, V S Manu, Matthew Walters, Larry Masterson, Marsha Rich Rosner, Alfonso De Simone, Gianluigi Veglia

{"title":"Protein Kinase A Phosphorylates a Conformationally High-Energy State of Raf Kinase Inhibitory Protein.","authors":"Cristina Olivieri, Carmen Biancaniello, V S Manu, Matthew Walters, Larry Masterson, Marsha Rich Rosner, Alfonso De Simone, Gianluigi Veglia","doi":"10.1016/j.jmb.2025.169466","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169466","url":null,"abstract":"Protein kinase A (PKA) is found in all mammalian tissues and plays a critical role in mediating many signaling processes. The structure and phosphorylation mechanism of the catalytic subunit of PKA (PKA-C) have been extensively studied in interactions with linear pseudosubstrate inhibitors, peptide substrates, or protein fragments. To date, however, there have been only a few studies examining how PKA recognizes full-length, folded proteins. Here, we utilized solution NMR spectroscopy and combination with replica-averaged restrained molecular dynamics (RARMD) calculations to investigate the interactions between PKA-C and Raf Kinase Inhibitory Protein (RKIP). RKIP is a member of the phosphatidylethanolamine binding protein (PEBP) family, which regulates important kinase pathways such as the Raf/MAPK pathway and the β-adrenergic receptor/cAMP-dependent PKA signaling cascade. The X-ray structure of RKIP reveals a compact fold, with the phosphorylation consensus sequence well-structured and essentially inaccessible to the kinase. Using Carr-Purcell-Meiboom-Gill (CPMG) and chemical exchange saturation transfer (CEST) experiments, we discovered that RKIP undergoes a conformational equilibrium between a compact fold and a more open conformation, where the C-terminal helix splays away from the RKIP core and exposes its phosphorylation sequence, allowing the kinase to bind and phosphorylate the substrate. The dynamic interplay between the kinase and the substrate may represent a common mechanism for kinases to recognizes well-folded substrates.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169466"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel HMBC-CC-HMQC NMR Strategy for Methyl Assignment Using Triple-¹³C-Labeled α-Ketoisovalerate Integrated with UCBShift 2.0. 结合UCBShift 2.0的新型HMBC-CC-HMQC核磁共振配甲基策略

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2025-09-26 DOI: 10.1016/j.jmb.2025.169465

Sonja Knödlstorfer, Giorgia Toscano, Aleksandra L Ptaszek, Georg Kontaxis, Federico Napoli, Jakob Schneider, Katharina Maier, Anna Kapitonova, Roman J Lichtenecker, Paul Schanda, Robert Konrat

{"title":"A Novel HMBC-CC-HMQC NMR Strategy for Methyl Assignment Using Triple-13C-Labeled α-Ketoisovalerate Integrated with UCBShift 2.0.","authors":"Sonja Knödlstorfer, Giorgia Toscano, Aleksandra L Ptaszek, Georg Kontaxis, Federico Napoli, Jakob Schneider, Katharina Maier, Anna Kapitonova, Roman J Lichtenecker, Paul Schanda, Robert Konrat","doi":"10.1016/j.jmb.2025.169465","DOIUrl":"10.1016/j.jmb.2025.169465","url":null,"abstract":"In this study, we describe an integrated approach for methyl group assignment comprising precursor-based selective methyl group labeling, a novel pulse sequence for methyl to backbone coherence transfer and chemical shift predictions using UCBShift 2.0. The utility of this novel α-ketoacid isotopologue is shown by the adaptation of an HMBC-HMQC pulse sequence that simultaneously connects geminal methyl groups of leucine and valine residues to each other and to the protein backbone. By additional 13C,2H-labeling of residues other than valine and leucine residues of the protein, important chemical shift information about neighboring residues (following valine and leucine residues) can be achieved. Thus, different valine and leucine residues in a protein can be characterized as a specific chemical shift vector. Frequency matching with predicted chemical shifts via UCBShift 2.0 using experimental data taken from a subset of the BMRB database revealed a correct assignment performance of about 90%. With applications to proteins of 60.2 kDa and 134 kDa (4 × 33.5 kDa) in size, we demonstrate that the approach provides valuable information even for very large proteins.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169465"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184498","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