Journal of Biological Chemistry最新文献_第2页

Colchicine inhibits vascular calcification by suppression inflammasome activation through the enhancement of the Sirt2-PP2Ac signaling pathway 秋水仙碱通过增强Sirt2-PP2Ac信号通路抑制炎性体激活，从而抑制血管钙化

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.jbc.2025.110381

Shu Yang, Heming Huang, Kewei Jiang, Ying Peng, Zhen Liang, Xinyu Gong, Lixing Li, Yanchun Li, Buchun Zhang, Yuanli Chen, Xiaoxiao Yang

{"title":"Colchicine inhibits vascular calcification by suppression inflammasome activation through the enhancement of the Sirt2-PP2Ac signaling pathway","authors":"Shu Yang, Heming Huang, Kewei Jiang, Ying Peng, Zhen Liang, Xinyu Gong, Lixing Li, Yanchun Li, Buchun Zhang, Yuanli Chen, Xiaoxiao Yang","doi":"10.1016/j.jbc.2025.110381","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110381","url":null,"abstract":"Colchicine (Col) is a traditional herbal medicine derived from the plant <ce:italic>Colchicum autumnale</ce:italic>. With the property of anti-inflammation, Col has been demonstrated certain therapeutic effects in cardiovascular diseases (CVDs). Vascular calcification is positively related to the morbidity and mortality of CVDs. However, the specific cardiovascular conditions for which Col is effective remain unclear, particularly its impact on vascular calcification. In this study, we used high phosphate to induced calcium deposition in vascular smooth muscle cells (VSMCs), and Vitamin D3 plus nicotine or 5/6 nephrectomy along with high phosphate diet to construct vascular calcification mouse models. Our results showed that Col reduced calcium accumulation <ce:italic>in vitro</ce:italic>, and vascular calcification both in <ce:italic>ex-vivo</ce:italic> and <ce:italic>in vivo</ce:italic> models, which was evidenced by the Alizarin red S staining and calcium content determination. <ce:italic>In vitro</ce:italic> results showed that Col inhibited vascular calcification is contributed to the reduction of NLRP3 inflammasome activation through enhanced phosphorylation at Ser 5. In addition, we indicated that phosphorylation of NLRP3 is regulated by the activity of protein phosphatase 2Ac (PP2Ac). Furthermore, we identified that Sirt2 as a master regulator of PP2Ac activation through regulation its acetylation at Lys 136. More importantly, we demonstrated that Col-inhibited vascular calcification is dependent on Sirt2 expression by using the Sirt2 knockout mice. We demonstrate that Col protects vascular calcification. Our study provides novel insight into the clinical application of Col. We also suggest that Sirt2 is a novel target for vascular calcification treatment, and that Col may act as an activator of Sirt2, which could be beneficial in other diseases.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"51 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305072","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

Cytochrome P450BM-3 and P450 11A1 retain Compound I (FeO3+) chemistry with electrophilic substrates poised for Compound 0 (Fe3+O2¯) reactions 细胞色素P450BM-3和P450 11A1保留了化合物I （FeO3+）与亲电底物的化学反应，准备进行化合物0 （Fe3+O2¯）的反应

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.jbc.2025.110378

Kevin D. McCarty, Yasuhiro Tateishi, F. Peter Guengerich

{"title":"Cytochrome P450BM-3 and P450 11A1 retain Compound I (FeO3+) chemistry with electrophilic substrates poised for Compound 0 (Fe3+O2¯) reactions","authors":"Kevin D. McCarty, Yasuhiro Tateishi, F. Peter Guengerich","doi":"10.1016/j.jbc.2025.110378","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110378","url":null,"abstract":"The catalytic cycle of cytochrome P450 (P450) enzymes involves ferric peroxide anion (Fe<ce:sup loc=\"post\">3+</ce:sup>O<ce:inf loc=\"post\">2</ce:inf>¯, Compound 0) and perferryl oxygen (FeO<ce:sup loc=\"post\">3+</ce:sup>, Compound I) intermediates. Compound I is generally viewed as responsible for most P450-catalyzed oxidations, but Compound 0 has been implicated in the oxidation of some carbonyl compounds, particularly deformylation reactions. We considered the hypothesis that Compound 0 could also attack other electrophilic carbon atoms and accordingly positioned keto groups at preferred hydroxylation sites of substrates for two P450s with well-defined catalytic reactions, bacterial P450<ce:inf loc=\"post\">BM-3</ce:inf> (102A1) and human P450 11A1. The predicted products of Compound I and Compound 0 reactions were analyzed. With the normally preferred ω-1 site blocked, P450<ce:inf loc=\"post\">BM-3</ce:inf> oxidized 12-oxotridecanoic acid (12-oxo C13:0) only at the ω-2 position (yielding 11-hydroxy,12-oxotridecanoic acid), indicative of a Compound I oxidation. P450 11A1 is highly selective for catalyzing the 22<ce:italic>R</ce:italic>-hydroxylation of cholesterol (and some other sterols) in the first step of its overall side-chain cleavage reaction. With 22-oxocholesterol as the substrate, P450 11A1 (slowly) generated only 23-hydroxy,22-oxocholesterol, indicative of Compound I oxidation. Neither P450 generated the products expected from nucleophilic Compound 0 reactions. We conclude that the strategic placement of electrophilic oxo substituents at sites of substrate hydroxylation failed to divert the oxidation mechanism to a Compound 0 pathway with either enzyme. Instead, the Compound I mechanism – blocked at the preferred reaction site – was redirected to neighboring carbons, suggesting that the basis for Compound 0-mediated reactions lies in chemical properties of the enzyme rather than those of the substrate.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305074","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

Molecular basis for Gβγ-SNARE mediated inhibition of synaptic vesicle fusion. Gβγ-SNARE介导的突触囊泡融合抑制的分子基础。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.jbc.2025.110377

Anna R. Eitel, Benjamin K. Mueller, Ali I. Kaya, Montana Young, Jackson B. Cassada, Eric W. Bell, Lauren Schnitkey, Zack Zurawski, Yun Y. Yim, Qiangjun Zhou, Jens Meiler, Heidi E. Hamm

{"title":"Molecular basis for Gβγ-SNARE mediated inhibition of synaptic vesicle fusion.","authors":"Anna R. Eitel, Benjamin K. Mueller, Ali I. Kaya, Montana Young, Jackson B. Cassada, Eric W. Bell, Lauren Schnitkey, Zack Zurawski, Yun Y. Yim, Qiangjun Zhou, Jens Meiler, Heidi E. Hamm","doi":"10.1016/j.jbc.2025.110377","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110377","url":null,"abstract":"Neurotransmitter release is a complex process involving tightly controlled co-factors and protein-protein interactions. G protein coupled receptors negatively regulate exocytosis via the interaction of G-protein βγ (Gβγ) heterodimers with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. The neuronal ternary SNARE complex comprises synaptosomal-associated protein-25 (SNAP25), syntaxin-1A, and synaptobrevin-2. The regions of the SNARE complex that are important for interactions with Gβγ have been extensively characterized, but the critical sites on Gβγ are not well understood. Furthermore, the molecular basis for the specificity of different Gβ and Gγ isoforms for SNARE proteins remains elusive. Thus, we holistically probed the entire family of human Gβ and Gγ isoforms for regions critical for the target-SNARE (tSNARE) interaction using a peptide screening approach. Gβ and γ peptides with high affinities for tSNARE were then subjected to alanine scanning mutagenesis to identify the interaction sites. We found that the N-terminal coiled-coil domain of Gβγ as well as the β-propeller domain of Gβ are hotspots for SNARE interactions. Additionally, we found that the N-terminal Gγ2 peptide is a potent inhibitor of interactions between full-length Gβ1γ2 and SNAP25. We discovered that Gβ1γ2 preferentially interacts with ternary SNARE in the pre-fusion, partially zipped conformation, likely due to increased exposure of the C-terminus of SNAP25. Our combined results suggest that specific Gβγ heterodimers bind to ternary SNARE in the docked and primed state via critical residues of the β-propeller and N-terminal coil-coil domains. We propose that Gβγ binding disrupts zippering up the SNARE complex and thereby vesicle fusion.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"43 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304983","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

CH−π Interactions Confer Orientational Flexibility in Protein–Carbohydrate Binding Sites CH−π相互作用赋予蛋白质-碳水化合物结合位点的取向灵活性

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.jbc.2025.110379

Allison M. Keys, David W. Kastner, Laura L. Kiessling, Heather J. Kulik

{"title":"CH−π Interactions Confer Orientational Flexibility in Protein–Carbohydrate Binding Sites","authors":"Allison M. Keys, David W. Kastner, Laura L. Kiessling, Heather J. Kulik","doi":"10.1016/j.jbc.2025.110379","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110379","url":null,"abstract":"Protein−carbohydrate binding plays an essential role in biological processes including cellular recognition and immune signaling. However, glycans are hydrophilic with limited hydrophobic surfaces, a challenge for selective recognition by proteins. CH–π stacking interactions are pervasive in protein-carbohydrate binding sites and have emerged as critical drivers of protein–carbohydrate recognition. They are highly favorable and have a broad orientational landscape. However, it is unknown how CH−π stacking interaction orientational dynamics are influenced by the protein environment and what their functional interplay is with hydrogen bonds in protein–carbohydrate binding. Here, we employ well-tempered metadynamics simulations to obtain binding free energy landscapes for a set of protein−β-D-galactoside complexes with CH–π stacking interactions. Our data show that the favored orientation of a CH−π stacking interaction is controlled by the location of hydrogen bonds in the protein binding site. Complexes with extended carbohydrate ligands that form additional hydrogen bonds have more specific orientational dependences, while protein variant complexes with fewer hydrogen bonds have broader free energy landscapes with glycan ligands adopting multiple CH−π stacking interaction orientations. We also show that forming multiple CH−π stacking interactions facilitates the dynamics necessary for the translocation of oligosaccharide ligands within a processive enzyme. Our findings underscore the cooperative nature of hydrogen bonds and CH−π stacking interactions, demonstrating that tuning the number and positions of these interactions through evolution or protein engineering can alter ligand recognition or support ligand movement in protein binding sites.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"40 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305075","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

Targeted incorporation of collagen IV to the basement membrane: a step forward for developing extracellular protein therapies IV型胶原蛋白与基底膜的靶向结合：细胞外蛋白治疗的新进展

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.jbc.2025.110384

Elena N. Pokidysheva, Sara F. Tufa, Douglas R. Keene, Billy G. Hudson, Sergei P. Boudko

{"title":"Targeted incorporation of collagen IV to the basement membrane: a step forward for developing extracellular protein therapies","authors":"Elena N. Pokidysheva, Sara F. Tufa, Douglas R. Keene, Billy G. Hudson, Sergei P. Boudko","doi":"10.1016/j.jbc.2025.110384","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110384","url":null,"abstract":"The collagen IV scaffold serves as a fundamental structural unit of the basement membrane (BM). Understanding its structure, assembly, and function is essential for tissue engineering, design of organoid models, and developing therapies for diseases such as Alport syndrome, Gould syndrome, psoriasis, eye abnormalities, hearing loss, and others where collagen IV is required for structural integrity and functionality of the BM. The collagen IV molecule is a 400 nm long heterotrimer, comprising non-collagenous 1 (NC1), collagenous, and 7S domains. The assembly of the collagen IV scaffold involves oligomerization of the C-terminal NC1 and the N-terminal 7S domains, along with lateral associations within the collagenous domain. However, the detailed architecture and assembly mechanisms of the collagen IV scaffold remain unclear. Here, we investigated the potency and mechanism of recombinant single-chain NC1 trimer incorporation into the collagen IV scaffold. We discovered that the NC1 trimer influences the overall assembly of the basement membrane by affecting the quality of the developing collagen IV scaffold in a dose-dependent manner, without impacting already established scaffolds. This interference occurs through the hexamerization of supplemented NC1 trimers with endogenous NC1 domains, as the NC1 trimer becomes sulfilimine crosslinked with the existing chains. Overall, the single-chain NC1 trimer of collagen IV is crucial for developing novel extracellular therapies in two main ways: 1) facilitating the delivery and incorporation of functional replacements like collagen IV fragments, and 2) inhibiting the formation of new basement membranes in conditions such as tumor growth and detrimental vascularization.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"23 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305070","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

Abstract 3064 Bioengineering with synthetic cells 3064生物工程与合成细胞

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.jbc.2025.110170

Kate Adamala

引用次数: 0

Abstract 1941 Enhanced cellular and transdermal delivery of the modified chromatin using cell-penetrating peptide display 1941年，利用细胞穿透肽展示增强了修饰染色质的细胞和透皮递送

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.jbc.2025.110152

Jeong Park, Xinghan Zhang, Yuxin Liang

引用次数: 0

Abstract 3060 Structures of the PI3Ka/KRas complex on lipid bilayers reveal the molecular mechanism of PI3Ka activation 摘要：脂质双分子层上PI3Ka/KRas复合物的结构揭示了PI3Ka活化的分子机制

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.jbc.2025.110140

Kliment Verba, Hayarpi Torosyan, Michael Paul, Brigitte Meyer, Allison Maker, Natalia Jura

引用次数: 0

Abstract 3061 Control of IP3 receptor trafficking at the ER-mitochondrial contact sites [摘要]er -线粒体接触位点IP3受体运输的控制

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.jbc.2025.110141

Gyorgy Hajnoczky, Mate Katona, David Weaver, Arijita Ghosh, Yubin Zhou, Lian He

引用次数: 0

Abstract 3030 Phage-Based Approaches to Eliminate or Alter Bacteria within Complex Microbial Communities 3030基于噬菌体的方法消除或改变复杂微生物群落中的细菌

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.jbc.2025.110167

Mark Mimee

引用次数: 0