Journal of Molecular Biology最新文献

Essential Roles of Conserved Pseudouridines in Helix 69 for Ribosome Dynamics in Translation.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-05 DOI: 10.1016/j.jmb.2025.169132

Xin Chen, Hong Jin

{"title":"Essential Roles of Conserved Pseudouridines in Helix 69 for Ribosome Dynamics in Translation.","authors":"Xin Chen, Hong Jin","doi":"10.1016/j.jmb.2025.169132","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169132","url":null,"abstract":"The widespread distribution of pseudouridine (Ψ), an isomer of the canonical uridine base, in RNA indicates its functional importance to the cell. In eukaryotes, it is estimated that around 2% of ribosomal RNA nucleotides are pseudouridines, most of which are located in functional regions of the ribosome. Defects in RNA pseudouridylation induce a range of detrimental effects from compromised cellular protein biosynthesis to disease phenotypes in humans. However, genome-wide changes to mRNA translation profiles by ribosomes lacking specific conserved pseudouridines have not been extensively studied. Here, using a new genomic method called 5PSeq and in vitro biochemistry, we investigated changes in ribosome dynamics and cellular translation profiles upon loss of Ψ2258 and Ψ2260 in helix 69, the two most conserved pseudouridines in the ribosome in yeast cells. We found that inhibiting the formation of these two pseudouridines challenges ribosomes to maintain the correct open reading frame and causes generally faster ribosome dynamics in translation. Furthermore, mutant ribosomes are more prone to pause while translating a subset of GC-rich codons, especially rare codons such as Arg (CGA) and Arg (CGG). These results demonstrate the presence of Ψ2258 and Ψ2260 contributes to the dynamics of the H69 RNA stem-loop, and helps to maintain functional interactions with the tRNAs as they move within the ribosome. The optimality of this ribosome-tRNA interaction is likely to be more critical for those limited tRNAs that decode rare codons. Consistent with the changes in ribosome dynamics, we observe that IRES-mediated translation is compromised in the mutant ribosome. These results explain the importance of Ψ2258 and Ψ2260 in H69 to maintain cellular fitness. The strong conservation of Ψ2258 and Ψ2260 in the ribosomes from bacteria to humans indicates their functional significance in modulating ribosome functions. We anticipate that the identified functions of these covalent modifications are conserved in other species.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169132"},"PeriodicalIF":4.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802128","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

ENsiRNA: A multimodality method for siRNA-mRNA and modified siRNA efficacy prediction based on geometric graph neural network.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-05 DOI: 10.1016/j.jmb.2025.169131

Wenchong Tan, Mingshu Dai, Shimin Ye, Xin Tang, Dawei Jiang, Dong Chen, Hongli Du

引用次数: 0

Corrigendum to “Prion Propagation is Dependent on Key Amino Acids in Charge Cluster 2 within the Prion Protein” [J. Mol. Biol. 435(4) (2023) 167925]

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-05 DOI: 10.1016/j.jmb.2025.169114

Savroop Bhamra , Parineeta Arora , Szymon W. Manka, Christian Schmidt, Craig Brown, Melissa L.D. Rayner, Peter-Christian Klöhn, Anthony R. Clarke , John Collinge , Parmjit S. Jat

引用次数: 0

gmx_RRCS: a precision tool for detecting subtle conformational dynamics in molecular simulations.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-04 DOI: 10.1016/j.jmb.2025.169129

Wei Han, Zhenghan Chen, Ming-Wei Wang, Qingtong Zhou

{"title":"gmx_RRCS: a precision tool for detecting subtle conformational dynamics in molecular simulations.","authors":"Wei Han, Zhenghan Chen, Ming-Wei Wang, Qingtong Zhou","doi":"10.1016/j.jmb.2025.169129","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169129","url":null,"abstract":"Understanding conformational changes in biomolecules is crucial for insights into their biological functions and drug design, often studied by molecular dynamics (MD) simulations. However, current measurements such as RMSD, RMSF, interface area, and minimum distances fail to capture subtle conformational changes, including hydrophobic packing. Our study introduces gmx_RRCS, a precision tool developed to detect subtle conformational dynamics in MD simulations by analyzing residue-residue contact scores (RRCS). This tool quantifies interaction strengths between residues, enabling systematic analysis of both major and subtle conformational changes. Its application in investigating the molecular recognition of peptide 20 by glucagon-like peptide-1 receptor quantified the interactions of specific peptide moieties with the receptor, identified crucial positions for receptor binding, and highlighted key receptor residues involved in peptide recognition throughout the MD simulation. In phosphoinositide 3-kinase alpha (PI3Kα), gmx_RRCS revealed distinct conformational states of oncogenic hotspot residues by quantifying subtle sidechain reorientations and salt bridge dynamics. Similarly, in nucleic acid systems, the tool distinguished differential binding mechanisms between ochratoxin A and norfloxacin by revealing unique interaction patterns at critical nucleobases correlating with binding affinities. The tool has been validated through the analysis of over 150 simulation trajectories, covering 40,000 ns of total simulation time and 20 systems. gmx_RRCS significantly advances structural/molecular biology studies by enhancing our understanding of protein conformational dynamics, thereby facilitating rational drug design. gmx_RRCS is freely available on GitHub (https://github.com/RuijinHospitalRCMSB/gmx_RRCS) and PyPI (https://pypi.org/project/gmx-RRCS).","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169129"},"PeriodicalIF":4.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794437","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

DeepAssembly2: A Web Server for Protein Complex Structure Assembly Based on Domain-Domain Interactions.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-04 DOI: 10.1016/j.jmb.2025.169128

Yuhao Xia, Yilin Pu, Suhui Wang, Jianan Zhuang, Dong Liu, Minghua Hou, Guijun Zhang

{"title":"DeepAssembly2: A Web Server for Protein Complex Structure Assembly Based on Domain-Domain Interactions.","authors":"Yuhao Xia, Yilin Pu, Suhui Wang, Jianan Zhuang, Dong Liu, Minghua Hou, Guijun Zhang","doi":"10.1016/j.jmb.2025.169128","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169128","url":null,"abstract":"Proteins often perform biological functions by forming complexes, thereby accurately predicting the structure of protein complexes is crucial to understanding and mastering their functions, as well as facilitating drug discovery. Protein monomeric structure prediction has made a breakthrough in recent years, but the accurate prediction of complex structure remains a challenge. In this work, we present DeepAssembly2, a web server for automatically assembling protein complex structure based on domain-domain interactions. First, the features are constructed according to the input complex sequence and monomeric structures, then these features are used to predict the inter-chain residue distance through a deep learning model, and finally, the complex structure is assembled under the guidance of inter-chain residue distances. Compared with the previously developed version, DeepAssembly2 is trained on a newly constructed inter-chain domain-domain interaction dataset. Meanwhile, several important features have been added, such as Interface Residue Propensity and Ultrafast Shape Recognition. In addition, we introduced the inter-chain residue distance from the AlphaFold-Multimer model to further improve the accuracy. Finally, we also integrate our recently developed model quality assessment method to select the output models. The performance of DeepAssembly2 is significantly improved compared with the previous version, and it is expected to provide new insights and an effective tool for drug development, vaccine design, etc. The web server of DeepAssembly2 is freely available at http://zhanglab-bioinf.com/DeepAssembly/.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169128"},"PeriodicalIF":4.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794486","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 SinR•SlrR heteromer attenuates transcription of a long operon of flagellar genes in Bacillus subtilis. SinR-SlrR 异构体可抑制枯草芽孢杆菌鞭毛基因长操作子的转录。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-03 DOI: 10.1016/j.jmb.2025.169123

Ayushi Mishra, Abby Jackson, Xindan Wang, Daniel B Kearns

{"title":"The SinR•SlrR heteromer attenuates transcription of a long operon of flagellar genes in Bacillus subtilis.","authors":"Ayushi Mishra, Abby Jackson, Xindan Wang, Daniel B Kearns","doi":"10.1016/j.jmb.2025.169123","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169123","url":null,"abstract":"During growth, Bacillus subtilis differentiates into subpopulations of motile individuals and non-motile chains, associated with dispersal and biofilm formation, respectively. The two cell types are dictated by the activity of the alternative sigma factor SigD encoded as the penultimate gene of the 27 kb long fla/che flagellar operon. The frequency of SigD-ON motile cells is increased by the heteromeric transcription factor SwrA•DegU that activates the fla/che promoter. Conversely, the frequency of motile cells is decreased by the heteromeric transcription factor SinR•SlrR, but the mechanism and location of inhibition is poorly understood. Here, using ChIP-Seq analysis, we determine the binding sites of the SinR•SlrR heteromer on the genome. We identified two sites within the fla/che operon that were both necessary and sufficient to attenuate transcript abundance by causing premature termination upstream of the gene that encodes SigD. Thus, cell motility and the transition to biofilm formation depend on the expression of a long operon governed by two opposing heteromeric transcription factors that operate at two different stages of the transcription cycle. More broadly, our study serves as a model for transcription factors that control transcriptional elongation and the regulation of long operons in bacteria.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169123"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787624","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

Cryo-EM reveals structural diversity in prolate-headed mycobacteriophage Mycofy1.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-03 DOI: 10.1016/j.jmb.2025.169126

Xiangyun Li, Qianqian Shao, Lin Li, Linlin Xie, Zhiyang Ruan, Qianglin Fang

引用次数: 0

GPx4 is bound to peroxidized membranes by a hydrophobic anchor.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-03 DOI: 10.1016/j.jmb.2025.169122

Qingyang Hu, Hantian You, Kenan Li, Luhua Lai, Chen Song

{"title":"GPx4 is bound to peroxidized membranes by a hydrophobic anchor.","authors":"Qingyang Hu, Hantian You, Kenan Li, Luhua Lai, Chen Song","doi":"10.1016/j.jmb.2025.169122","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169122","url":null,"abstract":"Ferroptosis is a form of cell death discovered in recent years, induced by excessive peroxidation of phospholipids. Glutathione peroxidase 4 (GPx4) is an intracellular enzyme that can repair the peroxidized phospholipids on membranes, thus regulating ferroptosis. By combining multiscale molecular dynamics (MD) simulations and experimental assays, we investigate the binding mechanisms of GPx4 on membranes. Using coarse-grained MD simulations, we found that L130 and its adjacent residues on GPx4 can form a stable and unique binding interface with PE/PS-rich and peroxidized membranes. Subsequent all-atom MD simulations verified the stability of the binding interface. The critical residue on the interface, L130, was inserted deeply into the membrane as a hydrophobic anchor and guided the reaction center toward the membrane surface. Enzyme activity assays and in vitro cell experiments showed that mutations of L130 resulted in weaker activities of the enzyme, probably caused by non-functional binding modes of GPx4 on membranes, as revealed by in silico simulations. This study highlights the crucial role of the hydrophobic residue, L130, in the proper anchoring of GPx4 on membranes, the first step of its membrane-repairing function.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169122"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787619","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

PERCEPTRON-XFMS: An Open-Source Web Server for Analysis of X-ray Footprinting with Mass Spectrometry Data.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-03 DOI: 10.1016/j.jmb.2025.169127

Maham Hamid, Muhammad Farhan Khalid, Shahid Khan, Safee Ullah Chaudhary

{"title":"PERCEPTRON-XFMS: An Open-Source Web Server for Analysis of X-ray Footprinting with Mass Spectrometry Data.","authors":"Maham Hamid, Muhammad Farhan Khalid, Shahid Khan, Safee Ullah Chaudhary","doi":"10.1016/j.jmb.2025.169127","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169127","url":null,"abstract":"PERCEPTRON-XFMS is a freely available web-based platform for automated X-ray Footprinting with Mass Spectrometry (XFMS) analysis. XFMS provides residue-specific information on protein solvent accessibility by determining hydroxyl radical modification towards investigating protein interactions and conformational changes. The approach can enableglobal identification of structural waters associated with surface and internal residues in a protein. Towards an integrative analysis of XFMS data, PERCEPTRON-XFMS (i) extracts and quantifies oxidation rates, (ii) computes dose-response curves, and (iii) calculates protection factors for modified residues. The webserver takes five input files: (i) LC-MS data (mzXML), (ii) Mascot search results, (iii) protein sequence (fasta), (iv) structure (PDB), and (v) solvent accessible surface area (SASA) values. The platform outputs (i) dose-response plots, (ii) protection factors, and (iii) centrality values of modified residues. For a convenient visualization of these results, the webserver also provides PDB files with protection factors, andcentrality scores as an output. This is the first integrative platform that seamlessly brings together experimental and computational measures of water dynamics; thus, providing a much-needed bioinformatics tool for both fundamental and applied protein science. PERCEPTRON-XFMS webserver is freely available at https://perceptronxfms.lums.edu.pk along with its source code, at https://data.mendeley.com/datasets/ssjxhyrtwc.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169127"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787621","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

Conformational and Functional Regulation of SET by Legumain Cleavage.

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-04-03 DOI: 10.1016/j.jmb.2025.169119

Carina Horak, Alexander C Wieland, Rupert Klaushofer, Peter Briza, Hans Brandstetter, Elfriede Dall

{"title":"Conformational and Functional Regulation of SET by Legumain Cleavage.","authors":"Carina Horak, Alexander C Wieland, Rupert Klaushofer, Peter Briza, Hans Brandstetter, Elfriede Dall","doi":"10.1016/j.jmb.2025.169119","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169119","url":null,"abstract":"The cysteine protease legumain typically localizes to the endolysosomal system, where it is an important player in the immune system. However, in the context of Alzheimer's disease (AD), legumain has been shown to be translocated to the cytosol, where it cleaves SET, synonymously termed TAF-1 or I2PP2A, an inhibitor of protein phosphatase 2A. SET is primarily found in the nucleus, where it regulates gene transcription, cell cycle progression, and histone acetylation, but can also translocate to the cytoplasm where it regulates cell migration and is implicated in neuronal apoptosis in AD. In this study, we demonstrate that legumain cleaves SET at two major sites: Asn16 at the N-terminal end and Asn175 at the earmuff domain. Contrary to previous findings, our biochemical and crystallographic experiments reveal that the corresponding N- and C-terminal cleavage products remain bound in a stable complex, rather than dissociating. Additionally, we show that the C-terminal acidic stretch of SET is essential for its binding to histone 1, and that cleavage impairs this interaction. Finally, we demonstrate that SET positively modulates PP2A activity. This effect is however abolished upon cleavage by legumain.","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169119"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787617","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