Molecular & Cellular Proteomics最新文献

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Driving Therapeutic Innovation in Neurodegenerative Disease with Hydrogen Deuterium eXchange Mass Spectrometry. 氢氘交换质谱技术推动神经退行性疾病治疗创新。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-20 DOI: 10.1016/j.mcpro.2025.101017
Andrea Pierangelini, Benedikt M Kessler, Darragh P O'Brien
{"title":"Driving Therapeutic Innovation in Neurodegenerative Disease with Hydrogen Deuterium eXchange Mass Spectrometry.","authors":"Andrea Pierangelini, Benedikt M Kessler, Darragh P O'Brien","doi":"10.1016/j.mcpro.2025.101017","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101017","url":null,"abstract":"<p><p>Human neurodegenerative conditions such as Parkinson's and Alzheimer's Disease are characterized by the formation and deposition of toxic protein species which exacerbate neuronal dysfunction, impacting the structure and function of the healthy brain. Deciphering the mechanisms underlying protein (mis)folding and aggregation is not only essential for a more coherent view of neurodegeneration, but also crucial for the development of novel therapeutics targeting this family of disorders. Key pathological drivers of neurodegeneration, such as alpha-synuclein and tau proteins, have traditionally proved extremely challenging to characterize structurally due to their intrinsic and widespread structural plasticity. Hydrogen-Deuterium eXchange Mass Spectrometry (HDX-MS) has emerged as a powerful tool to help circumvent this, owing to its ability to capture protein intrinsic disorder in solution, in addition to the transient structural conformations that typify protein aggregation pathways. This review brings together the most recent research where HDX-MS has shed light on mechanisms of neurodegeneration. We highlight how the technique has been successfully integrated into therapeutic development workflows targeting some of the most prevalent neurodegenerative diseases.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101017"},"PeriodicalIF":6.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369072","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
High throughput single-cell proteomics of in vivo cells. 体内细胞的高通量单细胞蛋白质组学。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-20 DOI: 10.1016/j.mcpro.2025.101018
Shiri Karagach, Joachim Smollich, Ofir Atrakchi, Vishnu Mohan, Tamar Geiger
{"title":"High throughput single-cell proteomics of in vivo cells.","authors":"Shiri Karagach, Joachim Smollich, Ofir Atrakchi, Vishnu Mohan, Tamar Geiger","doi":"10.1016/j.mcpro.2025.101018","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101018","url":null,"abstract":"<p><p>Single-cell mass spectrometry-based proteomics (SCP) can resolve cellular heterogeneity in complex biological systems and provide a system-level view of the proteome of each cell. Major advancements in SCP methodologies have been introduced in recent years, providing highly sensitive sample preparation methods and mass spectrometric technologies. However, most studies present limited throughput and mainly focus on the analysis of cultured cells. To enhance the depth, accuracy, and throughput of SCP for tumor analysis, we developed an automated, high-throughput pipeline that enables the analysis of 1,536 single cells in a single experiment. This approach integrates low-volume sample preparation, automated sample purification, and LC-MS analysis with the Slice-PASEF method. Integration of these methodologies into a streamlined pipeline led to a robust and reproducible identification of more than 3000 proteins per cell. We applied this pipeline to analyze tumor macrophages in a murine lung metastasis model. We identified over 1,700 proteins per cell, including key macrophage markers and more than 500 differentially expressed proteins between tumor and control macrophages. PCA analysis successfully separated these populations, revealing the utility of SCP in capturing biologically relevant signals in the tumor microenvironment. Our results demonstrate a robust and scalable pipeline poised to advance single-cell proteomics in cancer research.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101018"},"PeriodicalIF":6.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369073","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
Cytosolic WPRa4 and Plastoskeletal PMI4 Proteins Mediate Touch Response in a Model Organism Arabidopsis. 拟南芥模型生物细胞质WPRa4和塑性骨骼PMI4蛋白介导触摸反应。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-11 DOI: 10.1016/j.mcpro.2025.101015
Kebin Wu, Nan Yang, Jia Ren, Shichang Liu, Kai Wang, Shuaijian Dai, Yinglin Lu, Yuxing An, Fuyun Tian, Zhaobing Gao, Zhu Yang, Yage Zhang, Weichuan Yu, Ning Li
{"title":"Cytosolic WPRa4 and Plastoskeletal PMI4 Proteins Mediate Touch Response in a Model Organism Arabidopsis.","authors":"Kebin Wu, Nan Yang, Jia Ren, Shichang Liu, Kai Wang, Shuaijian Dai, Yinglin Lu, Yuxing An, Fuyun Tian, Zhaobing Gao, Zhu Yang, Yage Zhang, Weichuan Yu, Ning Li","doi":"10.1016/j.mcpro.2025.101015","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101015","url":null,"abstract":"<p><p>To elucidate the early signaling components involved in thigmomorphogenesis in Arabidopsis thaliana, we combined microscopy and proximity-labeling (PL)-based quantitative biotinylproteomics to characterize the touch-responsive putative cytoskeleton-interacting protein WPRa4. Our findings revealed that WPRa4 localizes near plastids and interacts with cytosolic Plastid Movement-Impaired (PMI) proteins and a plastidic translocon component, suggesting a cytoskeleton-plastid network in mechanosensing. Bioinformatic analysis of PL and cross-linking mass spectrometry (XL-MS) data identified PMI4 as a key mediator, with pmi4 mutants lacking touch-induced bolting delay, rosette size reduction, and Ca<sup>2+</sup> oscillations. Transcriptomics further showed that PMI4 regulates touch-responsive and jasmonic acid (JA)-associated genes, such as LOX2. We propose a molecular model where interconnected Cytoskeleton-Plastoskeleton Continuum (CPC) proteins act as early mechanosensors, integrating the touch responses of plant aerial organs with calcium signaling and transcriptional reprogramming in Arabidopsis.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101015"},"PeriodicalIF":6.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294106","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
DHODH blockade induces ferroptosis in neuroblastoma by modulating the mevalonate pathway. DHODH阻断通过调节甲羟戊酸途径诱导成神经细胞瘤铁下垂。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-11 DOI: 10.1016/j.mcpro.2025.101014
Jui-Chia Shih, Pin-Yu Chen, Chuan-Hao Kuo, Chiao-Hui Hsieh, Hsin-Yi Chang, Hong-Chih Lee, Chen-Hao Huang, Chun-Hua Hsu, Wen-Ming Hsu, Hsuan-Cheng Huang, Hsueh-Fen Juan
{"title":"DHODH blockade induces ferroptosis in neuroblastoma by modulating the mevalonate pathway.","authors":"Jui-Chia Shih, Pin-Yu Chen, Chuan-Hao Kuo, Chiao-Hui Hsieh, Hsin-Yi Chang, Hong-Chih Lee, Chen-Hao Huang, Chun-Hua Hsu, Wen-Ming Hsu, Hsuan-Cheng Huang, Hsueh-Fen Juan","doi":"10.1016/j.mcpro.2025.101014","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101014","url":null,"abstract":"<p><p>Neuroblastoma is the most common heterogeneous solid tumor in children, and current treatment options remain limited, especially for high-risk patients. Previous studies have identified dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine synthesis, as a potential therapeutic target in cancer. However, none of the existing FDA-approved DHODH inhibitors have shown effective inhibition of neuroblastoma cell growth. To address this challenge, we employed virtual screening to discover potential DHODH-targeting drugs, identifying Regorafenib as a promising candidate. Regorafenib significantly inhibited neuroblastoma growth in both neuroblastoma cells and patient-derived organoids. To unravel the underlying molecular mechanisms, we conducted Tandem Mass Tag (TMT)-based quantitative proteomics using LC-MS/MS. Our proteomic profiling revealed substantial regulation of lipid metabolism proteins, specifically those in the mevalonate pathway, correlating with ferroptosis induction. Further analysis showed that DHODH inhibition led to a reduction in total cholesterol, cholesterol esters, disrupted lipid droplet formation, and significantly decreased the expression of Squalene Epoxidase (SQLE), a key enzyme in lipid metabolism. Notably, we also observed an increase in nuclear SQLE expression following DHODH inhibition. In summary, our study highlights DHODH blockade as a novel approach to induce ferroptosis through lipid metabolism reprogramming, underscoring DHODH as a viable therapeutic target for neuroblastoma treatment. These insights open new avenues for metabolic-based interventions in aggressive pediatric cancers.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101014"},"PeriodicalIF":6.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294107","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
Identification of Small Open Reading Frame-encoded Peptides in Glioma by an Optimized Proteomics Strategy. 利用优化的蛋白质组学策略鉴定胶质瘤中开放阅读框编码的小肽。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-11 DOI: 10.1016/j.mcpro.2025.101016
Tingting Zhang, Jian Cheng, Jiao Li, Zixia Ye, Na Li, Jifeng Wang, Xiaojuan Yang, Yong Peng
{"title":"Identification of Small Open Reading Frame-encoded Peptides in Glioma by an Optimized Proteomics Strategy.","authors":"Tingting Zhang, Jian Cheng, Jiao Li, Zixia Ye, Na Li, Jifeng Wang, Xiaojuan Yang, Yong Peng","doi":"10.1016/j.mcpro.2025.101016","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101016","url":null,"abstract":"<p><p>Small open reading frame - encoded peptides (SEPs), translated from previously unannotated genomic regions, have emerged as important regulators in diverse physiological and pathological processes. While ribosome profiling and bioinformatics analysis can predict putative SEPs, mass spectrometry (MS) is the only method for their definitive identification. However, MS-based SEP detection faces significant challenges due to SEP's short length and low abundance. To address these limitations, we developed an ammonium formate - mediated C8 solid - phase enrichment (AmF-C8-SPE) strategy that significantly outperforms classic C8-SPE, yielding superior SEP identification with enhanced unique peptide ratios and sequence coverage. By coupling AmF-C8-SPE with fractionation and LC-MS/MS analysis of glioma samples from 18 patients, we identified 549 novel SEPs, 113 of which exhibited differential expression between tumors and adjacent normal tissues. Importantly, randomly selected SEPs were validated by MS spectral matching with synthetic peptides and by confirming recombinant fusion protein expression in cells. Furthermore, Mfuzz clustering and ROC curve analyses revealed SEPs associated with glioma progression. DeepLoc-based prediction followed by confocal microscopy imaging confirmed nuclear localization of two candidate SEPs (IP_613981 and SPROHSA206836). Therefore, this study establishes an optimized SEP identification approach and the first comprehensive SEP profiling in glioma, providing a valuable resource to discover novel glioma biomarker and therapeutic target.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101016"},"PeriodicalIF":6.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294108","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
Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy. 蛋白质组学分析揭示了FLExDUX4小鼠面部肩胛骨-肱骨肌营养不良模型中轮式跑步运动肌肉反应的性别二态性。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-09 DOI: 10.1016/j.mcpro.2025.101013
Yusuke Nishimura, Adam Bittel, Abhishek Jagan, Yi-Wen Chen, Jatin Burniston
{"title":"Proteomic profiling uncovers sexual dimorphism in the muscle response to wheel running exercise in the FLExDUX4 murine model of facioscapulohumeral muscular dystrophy.","authors":"Yusuke Nishimura, Adam Bittel, Abhishek Jagan, Yi-Wen Chen, Jatin Burniston","doi":"10.1016/j.mcpro.2025.101013","DOIUrl":"10.1016/j.mcpro.2025.101013","url":null,"abstract":"<p><p>FLExDUX4 is a murine experimental model of facioscapulohumeral muscular dystrophy (FSHD) characterized by chronic, low levels of leaky expression of the human full-length double homeobox 4 gene (DUX4-fl). FLExDUX4 mice exhibit mild pathologies and functional deficits similar to people affected by FSHD. Proteomic studies in FSHD could offer new insights into disease mechanisms underpinned by post-transcriptional processes. We used mass spectrometry-based proteomics to quantify the abundance of 1322 proteins in triceps brachii muscle, encompassing both male and female mice in control and free voluntary wheel running (VWR) in Wild-type (n=3) and FLExDUX4 (n=3) genotypes. We report the triceps brachii proteome of FLExDUX4 mice recapitulates key skeletal muscle clinical characteristics of human FSHD, including alterations to mitochondria, RNA metabolism, oxidative stress, and apoptosis. RNA-binding proteins exhibit a sex-specific difference in FLExDUX4 mice. Sexual dimorphism of mitochondrial protein adaptation to exercise was uncovered specifically in FLExDUX4 mice, where females increased, but males decreased mitochondrial proteins after a 6-week of VWR. Our results highlight the importance of identifying sex-specific diagnostic biomarkers to enable more reliable monitoring of FSHD therapeutic targets. Our data provides a resource for the FSHD research community to explore the burgeoning aspect of sexual dimorphism in FSHD.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101013"},"PeriodicalIF":6.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275391","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
From Discovery to Delivery: A Rapid and Targeted Proteomics Workflow for Monitoring Chinese Hamster Ovary Biomanufacturing. 从发现到交付:监测中国仓鼠卵巢生物制造的快速和靶向蛋白质组学工作流程。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-04 DOI: 10.1016/j.mcpro.2025.101011
Charles Eldrid, Ellie Hawke, Kathleen M Cain, Kate Meeson, Joanne Watson, Reynard Spiess, Luke Johnston, William Smith, Matthew Russell, Robyn Hoare, John Raven, Jean-Marc Schwartz, Magnus Rattray, Leon Pybus, Alan Dickson, Andrew Pitt, Perdita Barran
{"title":"From Discovery to Delivery: A Rapid and Targeted Proteomics Workflow for Monitoring Chinese Hamster Ovary Biomanufacturing.","authors":"Charles Eldrid, Ellie Hawke, Kathleen M Cain, Kate Meeson, Joanne Watson, Reynard Spiess, Luke Johnston, William Smith, Matthew Russell, Robyn Hoare, John Raven, Jean-Marc Schwartz, Magnus Rattray, Leon Pybus, Alan Dickson, Andrew Pitt, Perdita Barran","doi":"10.1016/j.mcpro.2025.101011","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101011","url":null,"abstract":"<p><p>Chinese hamster ovary (CHO) cells are the industrial workhorse for manufacturing biopharmaceuticals, including monoclonal antibodies. CHO cell line development requires a more data-driven approach for the accelerated identification of hyper-productive cell lines. Traditional methods, which rely on time-consuming hierarchical screening, often fail to elucidate the underlying cellular mechanisms driving optimal bioreactor performance. Big data analytics, coupled with advancements in 'omics' technologies, are revolutionizing the study of industrial cell lines. Translating this knowledge into practical methods widely utilized in industrial biomanufacturing remains a significant challenge. This study leverages discovery proteomics to characterize dynamic changes within the CHO cell proteome during a 14-day fed-batch bioreactor cultivation. Utilizing a global untargeted proteomics workflow on both a ZenoTOF 7600 and a Cyclic IMS QToF, we identify 3358 proteins and present a comprehensive data set that describes the molecular changes that occur within a well characterized host chassis. By mapping relative abundances to key cellular processes, eight protein targets were selected as potential biomarkers. The abundance of these proteins through the production run are quantified using a 15-minute targeted triple quadrupole (MRM) assay which provides a molecular level QC for cell viability. This discovery to target workflow has the potential to assist engineering of new chassis and provide simple read outs of successful bioreactor batches.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101011"},"PeriodicalIF":6.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248702","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
Soluble VCAM-1 may serve as a pharmacodynamic CSF marker to monitor BACE2 activity in non-human primates. 可溶性VCAM-1可作为非人类灵长类动物脑脊液药效学标志物监测BACE2活性。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-04 DOI: 10.1016/j.mcpro.2025.101012
Sarah K Tschirner, Joy Yu Zuchero, Jennifer A Getz, Stephan A Müller, Karsten Nalbach, Matthew E Kennedy, Joseph W Lewcock, Stefan F Lichtenthaler
{"title":"Soluble VCAM-1 may serve as a pharmacodynamic CSF marker to monitor BACE2 activity in non-human primates.","authors":"Sarah K Tschirner, Joy Yu Zuchero, Jennifer A Getz, Stephan A Müller, Karsten Nalbach, Matthew E Kennedy, Joseph W Lewcock, Stefan F Lichtenthaler","doi":"10.1016/j.mcpro.2025.101012","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101012","url":null,"abstract":"<p><p>The β-secretase β-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer's disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo and no biomarker is available allowing to monitor the extent of BACE2 inhibition in vivo, in particular in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes of non-human primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130 and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101012"},"PeriodicalIF":6.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248703","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
UniScore, a unified and universal measure for peptide identification by multiple search engines. UniScore是一种统一的、通用的多肽识别方法,可通过多个搜索引擎进行识别。
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-02 DOI: 10.1016/j.mcpro.2025.101010
Tsuyoshi Tabata, Akiyasu C Yoshizawa, Kosuke Ogata, Chih-Hsiang Chang, Norie Araki, Naoyuki Sugiyama, Yasushi Ishihama
{"title":"UniScore, a unified and universal measure for peptide identification by multiple search engines.","authors":"Tsuyoshi Tabata, Akiyasu C Yoshizawa, Kosuke Ogata, Chih-Hsiang Chang, Norie Araki, Naoyuki Sugiyama, Yasushi Ishihama","doi":"10.1016/j.mcpro.2025.101010","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101010","url":null,"abstract":"<p><p>We propose UniScore as a metric for integrating and standardizing the outputs of multiple search engines in the analysis of data-dependent acquisition (DDA) data from LC/MS/MS-based bottom-up proteomics. UniScore is calculated from the annotation information attached to the product ions alone by matching the amino acid sequences of candidate peptides suggested by the search engine with the product ion spectrum. The acceptance criteria are controlled independently of the score values by using the false discovery rate based on the target-decoy approach. Compared to other rescoring methods that use deep learning-based spectral prediction, larger amounts of data can be processed using minimal computing resources. When applied to large-scale global proteome data and phosphoproteome data, the UniScore approach outperformed each of the conventional single search engines examined (Comet, X! Tandem, Mascot and MaxQuant). Furthermore, UniScore could also be directly applied to peptide matching in chimeric spectra without any additional filters.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101010"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225898","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
Closer Peptide Repertoire Similarity of HLA-B*14:03 and HLA-B*27:05 Sheds Light on Ankylosing Spondylitis Susceptibility. HLA-B*14:03和HLA-B*27:05肽库相似性揭示强直性脊柱炎易感性
IF 6.1 2区 生物学
Molecular & Cellular Proteomics Pub Date : 2025-06-02 DOI: 10.1016/j.mcpro.2025.101008
Laura Cobos-Figueroa, Javier Robles-Parrado, Elisenda Alari-Pahissa, Begoña Galocha, Carmen Mir, Ana Pintor-Poveda, Eilon Barnea, Arie Admon, Pilar Lauzurica, Elena Lorente
{"title":"Closer Peptide Repertoire Similarity of HLA-B*14:03 and HLA-B*27:05 Sheds Light on Ankylosing Spondylitis Susceptibility.","authors":"Laura Cobos-Figueroa, Javier Robles-Parrado, Elisenda Alari-Pahissa, Begoña Galocha, Carmen Mir, Ana Pintor-Poveda, Eilon Barnea, Arie Admon, Pilar Lauzurica, Elena Lorente","doi":"10.1016/j.mcpro.2025.101008","DOIUrl":"https://doi.org/10.1016/j.mcpro.2025.101008","url":null,"abstract":"<p><p>The human major histocompatibility complex class I (HLA-I) gene HLA-B*27 is the main risk factor for the rheumatic disease ankylosing spondylitis (AS) through an unknown mechanism. However, in African populations, where B*27 is rare, the B*14:03 allotype is strongly associated with AS, while B*14:02, which only differs from B*14:03 at one residue (L156R), is not associated with the disease. Here, we have used large-scale mass spectrometry-based peptide sequencing to analyze the peptidomes of HLA-B*14:03, HLA-B*14:02, and HLA-B*27:05, obtaining more than 2000 peptide ligands for each molecule. Remarkably, we found 1011 ligands shared by the AS-associated HLA-B*27:05 and -B*14:03 alleles and not by the non-AS-associated B*14:02 allele. Surprisingly, although B*14:03 and B*27:05 differ by 15 amino acids in their peptide binding domain, they show a large overlap of their ligands (64 and 43% respectively), while B*14:03 and B*14:02, which differ by only one residue, show a lower degree of overlap (33-35%). B*14:03 peptide repertoire most resembles that of B*27:05 at the P1, P2, and P5 positions of the peptides, and differs most at the C-terminal position, where B*14:03 is more restrictive than B*27:05. We have modeled how the change at residue 156 of the two B*14 alleles could have a long-range indirect effect on residues P1, P2, and P5 of the peptide ligands, explaining the different amino acid distribution observed between the two B*14 subtypes at those positions. Most of the 1011 specific ligands of B*14:03 and B*27:05 presented R/K/A/G at P1, R at P2, and L/F at the C-terminal position. Of these 1,011 peptides, 10 have been previously identified as presented by the three HLA-B*27 subtypes most strongly associated with AS and are absent in non-associated subtypes, while four peptides from the HLA 169-181 region-previously implicated in the autoimmune pathogenesis of AS-were also identified, suggesting that differential peptide binding may influence disease development. In summary, our results show that the two AS-associated allotypes B*14:03 and B*27:05, but not the non-AS-associated allotype B*14:02, share very similar peptide repertoires and binding characteristics, supporting specific common peptide ligands of HLA-B*27:05 and B*14:03 as a mechanism to explain the development of ankylosing spondylitis.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101008"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225896","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
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