Molecular Systems Biology最新文献_第3页

Redesigning error control in cross-linking mass spectrometry enables more robust and sensitive protein-protein interaction studies. 在交联质谱中重新设计误差控制使蛋白质相互作用的研究更加稳健和敏感。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-01-01 Epub Date: 2024-12-09 DOI: 10.1038/s44320-024-00079-w

Boris Bogdanow, Max Ruwolt, Julia Ruta, Lars Mühlberg, Cong Wang, Wen-Feng Zeng, Arne Elofsson, Fan Liu

{"title":"Redesigning error control in cross-linking mass spectrometry enables more robust and sensitive protein-protein interaction studies.","authors":"Boris Bogdanow, Max Ruwolt, Julia Ruta, Lars Mühlberg, Cong Wang, Wen-Feng Zeng, Arne Elofsson, Fan Liu","doi":"10.1038/s44320-024-00079-w","DOIUrl":"10.1038/s44320-024-00079-w","url":null,"abstract":"Cross-linking mass spectrometry (XL-MS) allows characterizing protein-protein interactions (PPIs) in native biological systems by capturing cross-links between different proteins (inter-links). However, inter-link identification remains challenging, requiring dedicated data filtering schemes and thorough error control. Here, we benchmark existing data filtering schemes combined with error rate estimation strategies utilizing concatenated target-decoy protein sequence databases. These workflows show shortcomings either in sensitivity (many false negatives) or specificity (many false positives). To ameliorate the limited sensitivity without compromising specificity, we develop an alternative target-decoy search strategy using fused target-decoy databases. Furthermore, we devise a different data filtering scheme that takes the inter-link context of the XL-MS dataset into account. Combining both approaches maintains low error rates and minimizes false negatives, as we show by mathematical simulations, analysis of experimental ground-truth data, and application to various biological datasets. In human cells, inter-link identifications increase by 75% and we confirm their structural accuracy through proteome-wide comparisons to AlphaFold2-derived models. Taken together, target-decoy fusion and context-sensitive data filtering deepen and fine-tune XL-MS-based interactomics.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"90-106"},"PeriodicalIF":8.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

State of the interactomes: an evaluation of molecular networks for generating biological insights. 相互作用组的状态：对产生生物学见解的分子网络的评估。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-01-01 Epub Date: 2024-12-09 DOI: 10.1038/s44320-024-00077-y

Sarah N Wright, Scott Colton, Leah V Schaffer, Rudolf T Pillich, Christopher Churas, Dexter Pratt, Trey Ideker

{"title":"State of the interactomes: an evaluation of molecular networks for generating biological insights.","authors":"Sarah N Wright, Scott Colton, Leah V Schaffer, Rudolf T Pillich, Christopher Churas, Dexter Pratt, Trey Ideker","doi":"10.1038/s44320-024-00077-y","DOIUrl":"10.1038/s44320-024-00077-y","url":null,"abstract":"Advancements in genomic and proteomic technologies have powered the creation of large gene and protein networks (\"interactomes\") for understanding biological systems. However, the proliferation of interactomes complicates the selection of networks for specific applications. Here, we present a comprehensive evaluation of 45 current human interactomes, encompassing protein-protein interactions as well as gene regulatory, signaling, colocalization, and genetic interaction networks. Our analysis shows that large composite networks such as HumanNet, STRING, and FunCoup are most effective for identifying disease genes, while smaller networks such as DIP, Reactome, and SIGNOR demonstrate stronger performance in interaction prediction. Our study provides a benchmark for interactomes across diverse biological applications and clarifies factors that influence network performance. Furthermore, our evaluation pipeline paves the way for continued assessment of emerging and updated interaction networks in the future.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1-29"},"PeriodicalIF":8.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Bacterial live therapeutics for human diseases. 治疗人类疾病的活细菌疗法。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-12-01 Epub Date: 2024-10-23 DOI: 10.1038/s44320-024-00067-0

Elisabet Frutos-Grilo, Yamile Ana, Javier Gonzalez-de Miguel, Marcel Cardona-I-Collado, Irene Rodriguez-Arce, Luis Serrano

引用次数: 0

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach. 了解肾癌发生的生物学过程：一种综合的多组学方法。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-12-01 Epub Date: 2024-11-26 DOI: 10.1038/s44320-024-00072-3

Ricardo Cortez Cardoso Penha, Alexandra Sexton Oates, Sergey Senkin, Hanla A Park, Joshua Atkins, Ivana Holcatova, Anna Hornakova, Slavisa Savic, Simona Ognjanovic, Beata Świątkowska, Jolanta Lissowska, David Zaridze, Anush Mukeria, Vladimir Janout, Amelie Chabrier, Vincent Cahais, Cyrille Cuenin, Ghislaine Scelo, Matthieu Foll, Zdenko Herceg, Paul Brennan, Karl Smith-Byrne, Nicolas Alcala, James D Mckay

{"title":"Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.","authors":"Ricardo Cortez Cardoso Penha, Alexandra Sexton Oates, Sergey Senkin, Hanla A Park, Joshua Atkins, Ivana Holcatova, Anna Hornakova, Slavisa Savic, Simona Ognjanovic, Beata Świątkowska, Jolanta Lissowska, David Zaridze, Anush Mukeria, Vladimir Janout, Amelie Chabrier, Vincent Cahais, Cyrille Cuenin, Ghislaine Scelo, Matthieu Foll, Zdenko Herceg, Paul Brennan, Karl Smith-Byrne, Nicolas Alcala, James D Mckay","doi":"10.1038/s44320-024-00072-3","DOIUrl":"10.1038/s44320-024-00072-3","url":null,"abstract":"Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1282-1302"},"PeriodicalIF":8.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting. 细胞下 mRNA 动力学建模显示，核保留是限制速率的因素。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-12-01 Epub Date: 2024-11-15 DOI: 10.1038/s44320-024-00073-2

David Steinbrecht, Igor Minia, Miha Milek, Johannes Meisig, Nils Blüthgen, Markus Landthaler

{"title":"Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting.","authors":"David Steinbrecht, Igor Minia, Miha Milek, Johannes Meisig, Nils Blüthgen, Markus Landthaler","doi":"10.1038/s44320-024-00073-2","DOIUrl":"10.1038/s44320-024-00073-2","url":null,"abstract":"Eukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated mRNAs from over 9000 genes. In addition, we estimated transcript elongation rates. Many matured mRNAs have long nuclear half-lives, indicating nuclear retention as the rate-limiting step in the flow of mRNAs. In contrast, mRNA transcripts coding for transcription factors show fast kinetic rates, and in particular short nuclear half-lives. Differentially localized mRNAs have distinct rate constant combinations, implying modular regulation. Membrane stability is high for membrane-localized mRNA and cytosolic stability is high for cytosol-localized mRNA. mRNAs encoding target signals for membranes have low cytosolic and high membrane half-lives with minor differences between signals. Transcripts of nuclear-encoded mitochondrial proteins have long nuclear retention and cytoplasmic kinetics that do not reflect co-translational targeting. Our data and analyses provide a useful resource to study spatiotemporal gene expression regulation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1346-1371"},"PeriodicalIF":8.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Deep quantification of substrate turnover defines protease subsite cooperativity. 底物周转的深度定量确定了蛋白酶亚位点的合作性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-12-01 Epub Date: 2024-10-28 DOI: 10.1038/s44320-024-00071-4

Rajani Kanth Gudipati, Dimos Gaidatzis, Jan Seebacher, Sandra Muehlhaeusser, Georg Kempf, Simone Cavadini, Daniel Hess, Charlotte Soneson, Helge Großhans

{"title":"Deep quantification of substrate turnover defines protease subsite cooperativity.","authors":"Rajani Kanth Gudipati, Dimos Gaidatzis, Jan Seebacher, Sandra Muehlhaeusser, Georg Kempf, Simone Cavadini, Daniel Hess, Charlotte Soneson, Helge Großhans","doi":"10.1038/s44320-024-00071-4","DOIUrl":"10.1038/s44320-024-00071-4","url":null,"abstract":"Substrate specificity determines protease functions in physiology and in clinical and biotechnological applications, yet quantitative cleavage information is often unavailable, biased, or limited to a small number of events. Here, we develop qPISA (quantitative Protease specificity Inference from Substrate Analysis) to study Dipeptidyl Peptidase Four (DPP4), a key regulator of blood glucose levels. We use mass spectrometry to quantify >40,000 peptides from a complex, commercially available peptide mixture. By analyzing changes in substrate levels quantitatively instead of focusing on qualitative product identification through a binary classifier, we can reveal cooperative interactions within DPP4's active pocket and derive a sequence motif that predicts activity quantitatively. qPISA distinguishes DPP4 from the related C. elegans DPF-3 (a DPP8/9-orthologue), and we relate the differences to the structural features of the two enzymes. We demonstrate that qPISA can direct protein engineering efforts like the stabilization of GLP-1, a key DPP4 substrate used in the treatment of diabetes and obesity. Thus, qPISA offers a versatile approach for profiling protease and especially exopeptidase specificity, facilitating insight into enzyme mechanisms and biotechnological and clinical applications.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1303-1328"},"PeriodicalIF":8.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Identifying T-cell clubs by embracing the local harmony between TCR and gene expressions. 通过 TCR 与基因表达之间的局部和谐来识别 T 细胞俱乐部。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1038/s44320-024-00070-5

Yiping Zou, Jiaqi Luo, Lingxi Chen, Xueying Wang, Wei Liu, Ruo Han Wang, Shuai Cheng Li

{"title":"Identifying T-cell clubs by embracing the local harmony between TCR and gene expressions.","authors":"Yiping Zou, Jiaqi Luo, Lingxi Chen, Xueying Wang, Wei Liu, Ruo Han Wang, Shuai Cheng Li","doi":"10.1038/s44320-024-00070-5","DOIUrl":"10.1038/s44320-024-00070-5","url":null,"abstract":"T cell receptors (TCR) and gene expression provide two complementary and essential aspects in T cell understanding, yet their diversity presents challenges in integrative analysis. We introduce TCRclub, a novel method integrating single-cell RNA sequencing data and single-cell TCR sequencing data using local harmony to identify functionally similar T cell groups, termed 'clubs'. We applied TCRclub to 298,106 T cells across seven datasets encompassing various diseases. First, TCRclub outperforms the state-of-the-art methods in clustering T cells on a dataset with over 400 verified peptide-major histocompatibility complex categories. Second, TCRclub reveals a transition from activated to exhausted T cells in cholangiocarcinoma patients. Third, TCRclub discovered the pathways that could intervene in response to anti-PD-1 therapy for patients with basal cell carcinoma by analyzing the pre-treatment and post-treatment samples. Furthermore, TCRclub unveiled different T-cell responses and gene patterns at different severity levels in patients with COVID-19. Hence, TCRclub aids in developing more effective immunotherapeutic strategies for cancer and infectious diseases.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1329-1345"},"PeriodicalIF":8.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

XCMS-METLIN: data-driven metabolite, lipid, and chemical analysis. XCMS-METLIN：数据驱动的代谢物、脂质和化学分析。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI: 10.1038/s44320-024-00063-4

Martin Giera, Aries Aisporna, Winnie Uritboonthai, Linh Hoang, Rico J E Derks, Kara M Joseph, Erin S Baker, Gary Siuzdak

引用次数: 0

High-throughput protein characterization by complementation using DNA barcoded fragment libraries. 通过使用 DNA 条形码片段库进行互补，实现高通量蛋白质表征。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-11-01 Epub Date: 2024-10-07 DOI: 10.1038/s44320-024-00068-z

Bradley W Biggs, Morgan N Price, Dexter Lai, Jasmine Escobedo, Yuridia Fortanel, Yolanda Y Huang, Kyoungmin Kim, Valentine V Trotter, Jennifer V Kuehl, Lauren M Lui, Romy Chakraborty, Adam M Deutschbauer, Adam P Arkin

{"title":"High-throughput protein characterization by complementation using DNA barcoded fragment libraries.","authors":"Bradley W Biggs, Morgan N Price, Dexter Lai, Jasmine Escobedo, Yuridia Fortanel, Yolanda Y Huang, Kyoungmin Kim, Valentine V Trotter, Jennifer V Kuehl, Lauren M Lui, Romy Chakraborty, Adam M Deutschbauer, Adam P Arkin","doi":"10.1038/s44320-024-00068-z","DOIUrl":"10.1038/s44320-024-00068-z","url":null,"abstract":"Our ability to predict, control, or design biological function is fundamentally limited by poorly annotated gene function. This can be particularly challenging in non-model systems. Accordingly, there is motivation for new high-throughput methods for accurate functional annotation. Here, we used complementation of auxotrophs and DNA barcode sequencing (Coaux-Seq) to enable high-throughput characterization of protein function. Fragment libraries from eleven genetically diverse bacteria were tested in twenty different auxotrophic strains of Escherichia coli to identify genes that complement missing biochemical activity. We recovered 41% of expected hits, with effectiveness ranging per source genome, and observed success even with distant E. coli relatives like Bacillus subtilis and Bacteroides thetaiotaomicron. Coaux-Seq provided the first experimental validation for 53 proteins, of which 11 are less than 40% identical to an experimentally characterized protein. Among the unexpected function identified was a sulfate uptake transporter, an O-succinylhomoserine sulfhydrylase for methionine synthesis, and an aminotransferase. We also identified instances of cross-feeding wherein protein overexpression and nearby non-auxotrophic strains enabled growth. Altogether, Coaux-Seq's utility is demonstrated, with future applications in ecology, health, and engineering.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1207-1229"},"PeriodicalIF":8.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Author Correction: From coarse to fine: the absolute Escherichia coli proteome under diverse growth conditions. 作者更正：从粗到细：不同生长条件下大肠杆菌蛋白质组的绝对值。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-11-01 DOI: 10.1038/s44320-024-00062-5

Matteo Mori, Zhongge Zhang, Amir Banaei-Esfahani, Jean-Benoît Lalanne, Hiroyuki Okano, Ben C Collins, Alexander Schmidt, Olga T Schubert, Deok-Sun Lee, Gene-Wei Li, Ruedi Aebersold, Terence Hwa, Christina Ludwig

引用次数: 0