Molecular Systems Biology最新文献_第3页

Proteome-scale characterisation of motif-based interactome rewiring by disease mutations. 以蛋白质组尺度描述疾病突变导致的基于主题的相互作用组重配。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI: 10.1038/s44320-024-00055-4

Johanna Kliche, Leandro Simonetti, Izabella Krystkowiak, Hanna Kuss, Marcel Diallo, Emma Rask, Jakob Nilsson, Norman E Davey, Ylva Ivarsson

{"title":"Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.","authors":"Johanna Kliche, Leandro Simonetti, Izabella Krystkowiak, Hanna Kuss, Marcel Diallo, Emma Rask, Jakob Nilsson, Norman E Davey, Ylva Ivarsson","doi":"10.1038/s44320-024-00055-4","DOIUrl":"10.1038/s44320-024-00055-4","url":null,"abstract":"Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1025-1048"},"PeriodicalIF":8.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620413","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

Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer. 体细胞CpG高突变与癌症错配修复缺陷有关。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-07-18 DOI: 10.1038/s44320-024-00054-5

Aidan Flynn, Sebastian M Waszak, Joachim Weischenfeldt

{"title":"Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer.","authors":"Aidan Flynn, Sebastian M Waszak, Joachim Weischenfeldt","doi":"10.1038/s44320-024-00054-5","DOIUrl":"10.1038/s44320-024-00054-5","url":null,"abstract":"Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1006-1024"},"PeriodicalIF":8.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724009","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

Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages. MAPK p38 和 NFκB 在巨噬细胞炎症反应中的动态和组合编码。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-13 DOI: 10.1038/s44320-024-00047-4

Stefanie Luecke, Xiaolu Guo, Katherine M Sheu, Apeksha Singh, Sarina C Lowe, Minhao Han, Jessica Diaz, Francisco Lopes, Roy Wollman, Alexander Hoffmann

{"title":"Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages.","authors":"Stefanie Luecke, Xiaolu Guo, Katherine M Sheu, Apeksha Singh, Sarina C Lowe, Minhao Han, Jessica Diaz, Francisco Lopes, Roy Wollman, Alexander Hoffmann","doi":"10.1038/s44320-024-00047-4","DOIUrl":"10.1038/s44320-024-00047-4","url":null,"abstract":"Macrophages sense pathogens and orchestrate specific immune responses. Stimulus specificity is thought to be achieved through combinatorial and dynamical coding by signaling pathways. While NFκB dynamics are known to encode stimulus information, dynamical coding in other signaling pathways and their combinatorial coordination remain unclear. Here, we established live-cell microscopy to investigate how NFκB and p38 dynamics interface in stimulated macrophages. Information theory and machine learning revealed that p38 dynamics distinguish cytokine TNF from pathogen-associated molecular patterns and high doses from low, but contributed little to information-rich NFκB dynamics when both pathways are considered. This suggests that immune response genes benefit from decoding immune signaling dynamics or combinatorics, but not both. We found that the heterogeneity of the two pathways is surprisingly uncorrelated. Mathematical modeling revealed potential sources of uncorrelated heterogeneity in the branched pathway network topology and predicted it to drive gene expression variability. Indeed, genes dependent on both p38 and NFκB showed high scRNAseq variability and bimodality. These results identify combinatorial signaling as a mechanism to restrict NFκB-AND-p38-responsive inflammatory cytokine expression to few cells.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"898-932"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317837","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

A 'rich-get-richer' mechanism drives patchy dynamics and resistance evolution in antibiotic-treated bacteria. 富者愈富 "的机制推动了抗生素处理过的细菌的斑块动态和耐药性进化。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1038/s44320-024-00046-5

Emrah Şimşek, Kyeri Kim, Jia Lu, Anita Silver, Nan Luo, Charlotte T Lee, Lingchong You

{"title":"A 'rich-get-richer' mechanism drives patchy dynamics and resistance evolution in antibiotic-treated bacteria.","authors":"Emrah Şimşek, Kyeri Kim, Jia Lu, Anita Silver, Nan Luo, Charlotte T Lee, Lingchong You","doi":"10.1038/s44320-024-00046-5","DOIUrl":"10.1038/s44320-024-00046-5","url":null,"abstract":"Bacteria in nature often form surface-attached communities that initially comprise distinct subpopulations, or patches. For pathogens, these patches can form at infection sites, persist during antibiotic treatment, and develop into mature biofilms. Evidence suggests that patches can emerge due to heterogeneity in the growth environment and bacterial seeding, as well as cell-cell signaling. However, it is unclear how these factors contribute to patch formation and how patch formation might affect bacterial survival and evolution. Here, we demonstrate that a 'rich-get-richer' mechanism drives patch formation in bacteria exhibiting collective survival (CS) during antibiotic treatment. Modeling predicts that the seeding heterogeneity of these bacteria is amplified by local CS and global resource competition, leading to patch formation. Increasing the dose of a non-eradicating antibiotic treatment increases the degree of patchiness. Experimentally, we first demonstrated the mechanism using engineered Escherichia coli and then demonstrated its applicability to a pathogen, Pseudomonas aeruginosa. We further showed that the formation of P. aeruginosa patches promoted the evolution of antibiotic resistance. Our work provides new insights into population dynamics and resistance evolution during surface-attached bacterial growth.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"880-897"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321261","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

Molecular causality in the advent of foundation models. 基础模型出现时的分子因果关系。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-18 DOI: 10.1038/s44320-024-00041-w

Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez

引用次数: 0

µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics. μPhos：高维磷酸化蛋白质组学的可扩展灵敏平台。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-21 DOI: 10.1038/s44320-024-00050-9

Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier

{"title":"µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics.","authors":"Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier","doi":"10.1038/s44320-024-00050-9","DOIUrl":"10.1038/s44320-024-00050-9","url":null,"abstract":"Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations is crucial for further illuminating the functionality of the phosphoproteome. Here we describe µPhos ('microPhos'), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture and small tissue amounts in <8 h total processing time. By greatly minimizing transfer steps and liquid volumes, we demonstrate increased sensitivity, >90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify ~17,000 Class I phosphosites in a human cancer cell line using 20 µg starting material, and confidently localize ~6200 phosphosites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable. We employ µPhos to study drug- and time-dependent response signatures in a leukemia cell line, and by quantifying 30,000 Class I phosphosites in the mouse brain we reveal distinct spatial kinase activities in subregions of the hippocampal formation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"972-995"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437256","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

Identification of novel toxins associated with the extracellular contractile injection system using machine learning. 利用机器学习识别与细胞外收缩注射系统相关的新型毒素。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-07-28 DOI: 10.1038/s44320-024-00053-6

Aleks Danov, Inbal Pollin, Eric Moon, Mengfei Ho, Brenda A Wilson, Philippos A Papathanos, Tommy Kaplan, Asaf Levy

{"title":"Identification of novel toxins associated with the extracellular contractile injection system using machine learning.","authors":"Aleks Danov, Inbal Pollin, Eric Moon, Mengfei Ho, Brenda A Wilson, Philippos A Papathanos, Tommy Kaplan, Asaf Levy","doi":"10.1038/s44320-024-00053-6","DOIUrl":"10.1038/s44320-024-00053-6","url":null,"abstract":"Secretion systems play a crucial role in microbe-microbe or host-microbe interactions. Among these systems, the extracellular contractile injection system (eCIS) is a unique bacterial and archaeal extracellular secretion system that injects protein toxins into target organisms. However, the specific proteins that eCISs inject into target cells and their functions remain largely unknown. Here, we developed a machine learning classifier to identify eCIS-associated toxins (EATs). The classifier combines genetic and biochemical features to identify EATs. We also developed a score for the eCIS N-terminal signal peptide to predict EAT loading. Using the classifier we classified 2,194 genes from 950 genomes as putative EATs. We validated four new EATs, EAT14-17, showing toxicity in bacterial and eukaryotic cells, and identified residues of their respective active sites that are critical for toxicity. Finally, we show that EAT14 inhibits mitogenic signaling in human cells. Our study provides insights into the diversity and functions of EATs and demonstrates machine learning capability of identifying novel toxins. The toxins can be employed in various applications dependently or independently of eCIS.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"859-879"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788702","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

Alternative proteoforms and proteoform-dependent assemblies in humans and plants. 人类和植物中的替代蛋白形式和蛋白形式依赖性组装。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-25 DOI: 10.1038/s44320-024-00048-3

Claire D McWhite, Wisath Sae-Lee, Yaning Yuan, Anna L Mallam, Nicolas A Gort-Freitas, Silvia Ramundo, Masayuki Onishi, Edward M Marcotte

{"title":"Alternative proteoforms and proteoform-dependent assemblies in humans and plants.","authors":"Claire D McWhite, Wisath Sae-Lee, Yaning Yuan, Anna L Mallam, Nicolas A Gort-Freitas, Silvia Ramundo, Masayuki Onishi, Edward M Marcotte","doi":"10.1038/s44320-024-00048-3","DOIUrl":"10.1038/s44320-024-00048-3","url":null,"abstract":"The variability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where the loss of a domain may accompany complex formation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"933-951"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450929","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

A proximity proteomics pipeline with improved reproducibility and throughput. 可提高重现性和通量的近距离蛋白质组学管道。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-07-01 DOI: 10.1038/s44320-024-00049-2

Xiaofang Zhong, Qiongyu Li, Benjamin J Polacco, Trupti Patil, Aaron Marley, Helene Foussard, Prachi Khare, Rasika Vartak, Jiewei Xu, Jeffrey F DiBerto, Bryan L Roth, Manon Eckhardt, Mark von Zastrow, Nevan J Krogan, Ruth Hüttenhain

{"title":"A proximity proteomics pipeline with improved reproducibility and throughput.","authors":"Xiaofang Zhong, Qiongyu Li, Benjamin J Polacco, Trupti Patil, Aaron Marley, Helene Foussard, Prachi Khare, Rasika Vartak, Jiewei Xu, Jeffrey F DiBerto, Bryan L Roth, Manon Eckhardt, Mark von Zastrow, Nevan J Krogan, Ruth Hüttenhain","doi":"10.1038/s44320-024-00049-2","DOIUrl":"10.1038/s44320-024-00049-2","url":null,"abstract":"Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing hands-on time and enhancing quantitative reproducibility. We introduced a scalable PL pipeline integrating automated enrichment of biotinylated proteins in a 96-well plate format. Combining this with optimized quantitative MS based on data-independent acquisition (DIA), we increased sample throughput and improved protein identification and quantification reproducibility. We applied this pipeline to delineate subcellular proteomes across various compartments. Using the 5HT2A serotonin receptor as a model, we studied temporal changes of proximal interaction networks induced by receptor activation. In addition, we modified the pipeline for reduced sample input to accommodate CRISPR-based gene knockout, assessing dynamics of the 5HT2A network in response to perturbation of selected interactors. This PL approach is universally applicable to PL proteomics using biotinylation-based PL enzymes, enhancing throughput and reproducibility of standard protocols.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"952-971"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476993","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

Multicellular dynamics and wealth distribution in bacteria. 细菌的多细胞动力学和财富分配。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1038/s44320-024-00056-3

Kyle R Allison

引用次数: 0