Journal of Biological Chemistry最新文献_第3页

The deubiquitinase OTUD4 suppresses TAK1 kinase-dependent NF-κB signaling and inflammation. 去泛素酶OTUD4抑制TAK1激酶依赖的NF-κB信号传导和炎症。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-10-06 DOI: 10.1016/j.jbc.2025.110784

Zhaohui Liu,Xiaolong Wang,Lihui Wu,Li Min,Ying Sheng,Zhiming Sun,Yunfang Deng,Lin Miao,Yue Liu,Jiabing Li,Yu Zhao

{"title":"The deubiquitinase OTUD4 suppresses TAK1 kinase-dependent NF-κB signaling and inflammation.","authors":"Zhaohui Liu,Xiaolong Wang,Lihui Wu,Li Min,Ying Sheng,Zhiming Sun,Yunfang Deng,Lin Miao,Yue Liu,Jiabing Li,Yu Zhao","doi":"10.1016/j.jbc.2025.110784","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110784","url":null,"abstract":"Chronic inflammation contributes to the development of many cancers, including non-small cell lung cancer (NSCLC), and is characterized by persistent activation of pro-inflammatory NF-κB signaling. The mechanisms that restrain NF-κB signaling remain incompletely defined. Here, we identify the deubiquitinase OTUD4 as a suppressor of tumor necrosis factor (TNF)-induced NF-κB activation and chronic inflammation. OTUD4 interacts with core components of the TAK1 signalosome, including TAK1, TAB1, and TAB3, and removes K63-linked polyubiquitin chains from substrates within this complex, such as TAK1 and TAB3, thereby reducing TNF-induced NF-κB signaling. A histidine-centered loop (His loop) in the catalytic domain is required for this K63 linkage specificity. The tumor-associated OTUD4 H148Y missense variant (c.442C>T, p.H148Y), located within this loop, retains TAK1 binding but abolishes intrinsic deubiquitinase activity toward both K63- and K48-linked chains and is associated with sustained NF-κB activation and increased pro-inflammatory cytokine expression. Collectively, these results reveal a mechanism that suppresses TNF-induced NF-κB signaling and links OTUD4 dysfunction to inflammation-driven oncogenesis, including NSCLC.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"33 1","pages":"110784"},"PeriodicalIF":4.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246788","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

Microphysiological Systems as a Pillar of the Human Exposome Project. 微生理系统作为人体暴露计划的支柱。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-10-04 DOI: 10.1016/j.jbc.2025.110782

Fenna Sillé,Lena Smirnova,Thomas Hartung

{"title":"Microphysiological Systems as a Pillar of the Human Exposome Project.","authors":"Fenna Sillé,Lena Smirnova,Thomas Hartung","doi":"10.1016/j.jbc.2025.110782","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110782","url":null,"abstract":"The Human Exposome Project (HEP) aims to decode how lifelong environmental exposures shape health and disease, complementing genomic insights with a systems-level understanding of external influences. Achieving this vision requires experimental platforms that move beyond the limitations of animal models, which often lack human relevance and mechanistic resolution. Microphysiological systems (MPS)-including organoids and organs-on-chips derived from human stem cells-offer such an opportunity. These engineered models recapitulate human tissue architecture and function under controlled conditions, enabling direct study of exposure-response relationships at the cellular and organ level. In this review, we outline how MPS can serve as a foundation for exposome research by bridging epidemiological observations with mechanistic biology. We describe applications ranging from air pollutant toxicity to food contaminants, endocrine disruptors, and nanomaterials, highlighting how MPS integrated with omics technologies and artificial intelligence (AI) can reveal pathways of injury, identify biomarkers, and support the development of digital twins to simulate exposure-disease trajectories. We also discuss frameworks for validation, quality assurance, and transparent reporting, which are essential for reproducibility and regulatory acceptance. Finally, we consider ethical issues such as donor rights, data sovereignty, and equitable access, underscoring the importance of anticipatory governance. Together, MPS represent more than alternatives to animal testing-they are strategic enablers of a human-relevant, AI-empowered exposome science. By anchoring statistical associations in mechanistic data, MPS can accelerate translation into public health policies that are predictive, preventive, and personalized.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"10 1","pages":"110782"},"PeriodicalIF":4.8,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235866","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 E3 ubiquitin ligase SPRYD3-MYCBP2(PAM) regulates mitotic cell fate and ubiquitination of USP11 to control spindle assembly. E3泛素连接酶SPRYD3-MYCBP2（PAM）调节有丝分裂细胞命运和USP11泛素化，控制纺锤体组装。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-10-04 DOI: 10.1016/j.jbc.2025.110785

Alexandra Rita Turi da Fonte Dias,Ingrid Hoffmann

引用次数: 0

A systematic comparison of in-house prepared transfection reagents in the delivery of mRNA or DNA to a wide range of cultured cells. 系统比较内部制备的转染试剂在mRNA或DNA传递到广泛的培养细胞中的作用。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-10-03 DOI: 10.1016/j.jbc.2025.110742

Ravi Ojha,Emilia Timin,Leonora Szirovicza,Wujun Xu,Jussi Hepojoki

{"title":"A systematic comparison of in-house prepared transfection reagents in the delivery of mRNA or DNA to a wide range of cultured cells.","authors":"Ravi Ojha,Emilia Timin,Leonora Szirovicza,Wujun Xu,Jussi Hepojoki","doi":"10.1016/j.jbc.2025.110742","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110742","url":null,"abstract":"Transfection is a fundamental molecular biology technique, enabling gene editing, protein expression, and vaccine development. However, transfection efficiency and cytotoxicity vary widely between reagent and cell type, necessitating optimization. Commercial reagents such as Lipofectamine 2000 and FuGENE HD are widely used for their high efficiency, but they are expensive and the efficiency can associate with cytotoxicity. In-house alternatives such as linear polyethylenimine (PEI; 25 kDa and 40 kDa) and cationic lipids-1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-combined with dioleoylphosphatidylethanolamine (DOPE) offer cost-effective options, but their performance across diverse cell types and nucleic acid type (RNA or DNA) remains insufficiently characterized. This motivated us to systematically evaluate transfection efficiency, cytotoxicity, and complex stability of these in-house reagents (DOPE:DOTAP and DOPE:DOTMA tested at molar ratios of 0.5:1, 1:1, and 2:1) over a broad range of reagent to nucleic acid ratios, using plasmid DNA and mRNA encoding mCherry. We performed transfections across 14 cell lines derived from human, monkey, frog, snake, and rodent tissues. We utilized automated fluorescence microscopy for quantifying transfection efficiency, luminescence-based viability assays for cytotoxicity, and studied complex stability during storage at 4°C (0, 4, and 24 hours) through transfection. Results revealed cell line-dependent differences in transfection efficiency, and showed in-house cationic lipid formulations to have a high mRNA transfection efficiency with low cytotoxicity. Lipofectamine 2000 and PEI 40k formed the most stable DNA complexes, but with higher cytotoxicity. This study provides a comprehensive reference for selecting customizable, cost-effective transfection reagents for specific cell and nucleic acid types.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"3 1","pages":"110742"},"PeriodicalIF":4.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228993","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

S2Tag, a novel affinity tag for the capture and immobilization of coiled-coil proteins: application to the study of human β-cardiac myosin. S2Tag，一种用于捕获和固定螺旋状蛋白的新型亲和标签：在人β-心肌肌球蛋白研究中的应用。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.jbc.2025.110776

Bipasha Barua, Robert C Cail, Yale E Goldman, E Michael Ostap, Donald A Winkelmann

{"title":"S2Tag, a novel affinity tag for the capture and immobilization of coiled-coil proteins: application to the study of human β-cardiac myosin.","authors":"Bipasha Barua, Robert C Cail, Yale E Goldman, E Michael Ostap, Donald A Winkelmann","doi":"10.1016/j.jbc.2025.110776","DOIUrl":"10.1016/j.jbc.2025.110776","url":null,"abstract":"Single molecule and ensemble motility assays are powerful tools for investigating myosin activity. A key requirement for the quality and reproducibility of the data obtained with these methods is the mode of attachment of myosin to assay surfaces. We previously characterized the ability of a monoclonal antibody (10F12.3) to tether skeletal muscle myosin to nitrocellulose coated glass. Here, we identify the 11 amino-acid epitope (S2Tag) recognized by 10F12.3 in the coiled-coil S2 domain of myosin. To test the transferability of S2Tag, we inserted it into a wild-type β-cardiac myosin construct (WT-βCM) and evaluated its mechanochemistry. WT-βCM immobilized via S2Tag robustly propelled actin filaments in gliding assays and showed single-molecule actin displacements and attachment kinetics by optical trapping. Thus, the antibody attachment is effective for ensemble and single molecule assays. We inserted the S2Tag into a βCM construct containing a penetrant mutation (S532P-βCM) that causes dilated cardiomyopathy. Inclusion of S2Tag enabled quantitative mixed-motor gliding filament assays with WT-βCM. The analysis shows the S532P mutation results in a 60% decrease in gliding speed, yet the motor seems to produce the same force as WT-βCM. Importantly, S2Tag is a useful new tool for affinity capture of alpha-helical coiled coil proteins.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110776"},"PeriodicalIF":4.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206262","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

Evidence of an activity-enhancing conformational shift in Arabidopsis thaliana Plant Cysteine Oxidase 4 induced by binding of substrate or substrate-mimics. 拟南芥植物半胱氨酸氧化酶4结合底物或底物模拟物诱导的增强活性的构象转变的证据。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.jbc.2025.110770

R Latter,J C J Hintzen,L M N Shah,D M Gunawardana,R M Sher,M D White,J Mecinović,J L P Benesch,E Flashman

{"title":"Evidence of an activity-enhancing conformational shift in Arabidopsis thaliana Plant Cysteine Oxidase 4 induced by binding of substrate or substrate-mimics.","authors":"R Latter,J C J Hintzen,L M N Shah,D M Gunawardana,R M Sher,M D White,J Mecinović,J L P Benesch,E Flashman","doi":"10.1016/j.jbc.2025.110770","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110770","url":null,"abstract":"Plant cysteine oxidases (PCOs) are a family of O2-dependent, thiol dioxygenase enzymes that help to coordinate plant responses to flooding by determining the stability of hypoxia-related transcription factors, Group VII Ethylene Response Factors (ERF-VIIs). Under normoxia, PCOs use O2 to catalyse the oxidation of the Nt-Cys of ERF-VIIs. The resultant N-degron proceeds along the Cys/Arg N-degron pathway for degradation. Conversely, hypoxic conditions such as those experienced during flooding, decrease PCO activity, stabilising ERF-VIIs which proceed to upregulate hypoxia responsive genes, enabling adaptations to submergence. PCOs are a target for improving plant flood tolerance. Inhibition of PCOs may prepare plants for submergence by promoting upregulation of hypoxia responsive genes. Previous work identified small molecule inhibitors of AtPCO4 and demonstrated that their use as a pre-treatment improved seedling tolerance to subsequent anoxia exposure. In this work, the pursuit of a peptide-based inhibition approach led to the development of ERF-VII derived peptidomimetics with modified N-termini. Upon testing in vitro, the peptidomimetics unexpectedly enhanced, rather than inhibited, AtPCO4 activity. Furthermore, anaerobic preincubation of PCOs with substrate itself was found to induce a similar response. Hydrogen-deuterium exchange mass spectrometry indicated that preincubation with peptidomimetic induces a conformational change in PCO structure. This suggests that substrate binding under anaerobic conditions could promote \"conformational priming\" of AtPCO4, where flexible regions within or surrounding the active site adopt a conformation that favours enhanced enzymatic activity. These data are the first evidence for dynamic movement of PCO structures and may be of significance for post-hypoxia PCO activity in planta.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"76 1","pages":"110770"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203466","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

New insights into the crosstalk between endocannabinoids and sphingosine-1-phosphate. 内源性大麻素与鞘氨醇-1-磷酸串扰的新认识。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.jbc.2025.110781

Cinzia Rapino,Sara Standoli,Francesca Cencetti,Paola Bruni,Sergio Oddi,Mauro Maccarrone

{"title":"New insights into the crosstalk between endocannabinoids and sphingosine-1-phosphate.","authors":"Cinzia Rapino,Sara Standoli,Francesca Cencetti,Paola Bruni,Sergio Oddi,Mauro Maccarrone","doi":"10.1016/j.jbc.2025.110781","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110781","url":null,"abstract":"This review aims at highlighting the interplay between the endocannabinoids (eCBs) anandamide and 2-arachidonoylglycerol, and sphingosine-1-phosphate (S1P) signaling. The eCBs and S1P are bioactive compounds that exemplify a paradigm of crosstalk among lipid signals, with profound implications for physiological processes and disease pathogenesis. Cross-communication between eCBs and S1P occurs through multiple mechanisms: (i) receptor heterodimerization and co-regulation, (ii) mutual metabolic modulation, and (iii) integrated regulation of downstream effectors. The latter emerged as a key mechanism underlying the bidirectional interactions between eCBs and S1P, with functional overlaps that regulate several processes including inflammation, vascular function, and neuronal activity. In addition, cannabis-derived compounds (such as cannabidiol) can influence eCBs and S1P signaling, calling for further research into their therapeutic exploitation. Overall, the dynamic interplay between endogenous eCBs and S1P - as well as with exogenous cannabidiol - described here offers a compelling example of the complexity of interactions among bioactive lipids. A deeper mechanistic understanding of these relationships could pave the way to novel strategies in drug design and development, emphasizing the importance of integrated approaches in the study of bioactive lipid biochemistry.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"47 1","pages":"110781"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203879","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 Farnesoid X Receptor T296I Variant Disrupts Ligand-induced FXR Activation and thus Bile Acid Transport in Progressive Familial Intrahepatic Cholestasis. Farnesoid X受体T296I变异破坏配体诱导的FXR激活和胆汁酸运输在进行性家族性肝内胆汁淤积症中。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.jbc.2025.110769

Annika Behrendt,Alex Bastianelli,Jan Stindt,Eva-Doreen Pfister,Malte Sgodda,Tobias Cantz,Sebastian Hook,Mohanraj Gopalswamy,Kathrin Grau,Stefanie Brands,Carola Dröge,Amelie Stalke,Michele Bonus,Sabine Franke,Ulrich Baumann,Verena Keitel,Holger Gohlke

{"title":"A Farnesoid X Receptor T296I Variant Disrupts Ligand-induced FXR Activation and thus Bile Acid Transport in Progressive Familial Intrahepatic Cholestasis.","authors":"Annika Behrendt,Alex Bastianelli,Jan Stindt,Eva-Doreen Pfister,Malte Sgodda,Tobias Cantz,Sebastian Hook,Mohanraj Gopalswamy,Kathrin Grau,Stefanie Brands,Carola Dröge,Amelie Stalke,Michele Bonus,Sabine Franke,Ulrich Baumann,Verena Keitel,Holger Gohlke","doi":"10.1016/j.jbc.2025.110769","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110769","url":null,"abstract":"Nuclear receptor farnesoid X receptor (FXR) acts as a key regulator of bile acid pool homeostasis and metabolism. Within the enterohepatic circulation, reabsorbed bile acids act as FXR agonists, which transcriptionally controls the synthesis and transport of bile acids. Binding occurs in the ligand binding domain (LBD), favoring a conformational change to the active state in which helix 12 interacts with the LBD to form an interaction surface for nuclear co-activators. The homozygous missense variant T296I, identified in a progressive familial intrahepatic cholestasis (PFIC) patient, is located close to the critical helix 12 interaction. Here, we identified reduced transcriptional activity of the variant protein on the downstream targets bile salt export pump (BSEP) and small heterodimer partner (SHP) in vitro, within the patient's liver, and in iPSC-derived hepatic organoids. BSEP-dependent Tauro-DBD transport was impaired in T296I patient-derived organoids, but could be rescued via lipid nanoparticle-mediated FXR WT mRNA delivery, indicating the variant is responsible for the identified reduced BSEP expression. Using molecular dynamics simulations, we observed a reduced transitioning from the inactive to the active state for the T296I variant, indicating a molecular mechanism underlying the reduced activity. To our knowledge, this is the first study to describe the conformational change from an inactive to an active state of the FXR LBD. This might be useful for new therapeutic approaches targeting the activation of FXR.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"38 1","pages":"110769"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203457","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 a novel GREMLIN1 uptake pathway in epithelial cells that requires BMP binding. 上皮细胞中需要BMP结合的新的GREMLIN1摄取途径的鉴定。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.jbc.2025.110780

Zhichun Gao, Yuhan Gao, Louise R Dutton, Melibea Berzosa Suner, Grace Todd, Gregory R Gipson, Connor Browne, Emma M Kerr, Carole Daly, Bianca Plouffe, Philip D Dunne, Dessislava Malinova, Derek P Brazil

{"title":"Identification of a novel GREMLIN1 uptake pathway in epithelial cells that requires BMP binding.","authors":"Zhichun Gao, Yuhan Gao, Louise R Dutton, Melibea Berzosa Suner, Grace Todd, Gregory R Gipson, Connor Browne, Emma M Kerr, Carole Daly, Bianca Plouffe, Philip D Dunne, Dessislava Malinova, Derek P Brazil","doi":"10.1016/j.jbc.2025.110780","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110780","url":null,"abstract":"GREM1 binding to BMP targets in the extracellular matrix prevents their engagement with cognate BMP receptors, attenuating BMP-dependent signaling and gene expression. Some evidence suggests that GREM1 can directly bind to receptor tyrosine kinases on the plasma membrane, further complicating our understanding of GREM1 biology. To attempt to clarify the complexities of GREM1 signaling, we show that GREM1 protein is produced and secreted by intestinal fibroblasts and endocytosed by neighbouring epithelial cells. GREM1 uptake occurs by both clathrin- and caveolin-mediated endocytosis. Cell membrane heparin sulfate proteoglycans are required for GREM1 binding and uptake, and once internalised, GREM1 appears to localise to the early endosomes and can be resecreted. Addition of BMP2 enhanced GREM1 uptake into cells. Remarkably, generation of a BMP-resistant GREM1 mutant abolished GREM1 uptake both in the presence and absence of BMP2. These data suggest that GREM1 binding and uptake into cells requires BMP binding, a process that may contribute to the antagonism of BMP signaling by GREM1.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110780"},"PeriodicalIF":4.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206287","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

Missense mutations in intrinsically disordered protein regions link pathogenicity and phase separation. 内在无序蛋白质区域的错义突变将致病性和相分离联系起来。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.jbc.2025.110773

Oliver L Kipp, Karen A Lewis, Loren E Hough, Steven T Whitten

{"title":"Missense mutations in intrinsically disordered protein regions link pathogenicity and phase separation.","authors":"Oliver L Kipp, Karen A Lewis, Loren E Hough, Steven T Whitten","doi":"10.1016/j.jbc.2025.110773","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110773","url":null,"abstract":"The impact of missense genetic variations on protein function is often enigmatic, especially for mutations that map to intrinsically disordered regions (IDRs). Given the functional importance of phase separation of IDRs, it has been proposed that mutations that modulate phase separation might preferentially lead to disease. To examine this idea, we used the robust predictability of phase-separating (PS) IDRs and annotation of disease-associated proteins and mutations to map the correlation between disease and phase separation. Consistent with previous work linking phase separation to cancer and autism spectrum disorder, we find a higher prevalence of predicted phase separation behavior in disease-associated proteins than typical for human proteins. We map the prevalence of phase separation across a wide range of diseases, finding that many, but not all, show an enrichment of phase separation in the proteins associated with them. Strikingly, the pathogenic mutation rate in predicted PS IDRs was elevated three-fold relative to IDRs not predicted to phase separate. Substitutions involving arginine and the aromatic types were among the most pathogenic for PS IDRs, while substitutions involving serine, threonine, and alanine the most benign. We applied these trends to mutations of uncertain clinical significance and predict that half found in PS IDRs are likely pathogenic. We find that phosphorylation sites were enriched in PS IDRs when compared to other protein regions, though mutations at such sites were mostly benign. Pathogenicity was highest for mutations in predicted PS IDRs when also found in a short linear motif, known mediators of protein-protein interactions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110773"},"PeriodicalIF":4.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206298","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