The FEBS journal最新文献_第2页

Characterization of a membrane toxin-antitoxin system, tsaAT, from Staphylococcus aureus. 金黄色葡萄球菌膜毒素-抗毒素系统 tsaAT 的特征。

The FEBS journal Pub Date : 2024-11-01 Epub Date: 2024-10-02 DOI: 10.1111/febs.17289

Fuminori Kato, Risa Bandou, Yoshihiro Yamaguchi, Keiko Inouye, Masayori Inouye

{"title":"Characterization of a membrane toxin-antitoxin system, tsaAT, from Staphylococcus aureus.","authors":"Fuminori Kato, Risa Bandou, Yoshihiro Yamaguchi, Keiko Inouye, Masayori Inouye","doi":"10.1111/febs.17289","DOIUrl":"10.1111/febs.17289","url":null,"abstract":"Bacterial toxin-antitoxin (TA) systems consist of a toxin that inhibits essential cellular processes, such as DNA replication, transcription, translation, or ATP synthesis, and an antitoxin neutralizing their cognate toxin. These systems have roles in programmed cell death, defense against phage, and the formation of persister cells. Here, we characterized the previously identified Staphylococcus aureus TA system, tsaAT, which consists of two putative membrane proteins: TsaT and TsaA. Expression of the TsaT toxin caused cell death and disrupted membrane integrity, whereas TsaA did not show any toxicity and neutralized the toxicity of TsaT. Furthermore, subcellular fractionation analysis demonstrated that both TsaA and TsaT localized to the cytoplasmic membrane of S. aureus expressing either or both 3xFLAG-tagged TsaA and 3xFLAG-tagged TsaT. Taken together, these results demonstrate that the TsaAT TA system consists of two membrane proteins, TsaA and TsaT, where TsaT disrupts membrane integrity, ultimately leading to cell death. Although sequence analyses showed that the tsaA and tsaT genes were conserved among Staphylococcus species, amino acid substitutions between TsaT orthologs highlighted the critical role of the 6th residue for its toxicity. Further amino acid substitutions indicated that the glutamic acid residue at position 63 in the TsaA antitoxin and the cluster of five lysine residues in the TsaT toxin are involved in TsaA's neutralization reaction. This study is the first to describe a bacterial TA system wherein both toxin and antitoxin are membrane proteins. These findings contribute to our understanding of S. aureus TA systems and, more generally, give new insight into highly diverse bacterial TA systems.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EGF/EGFR-YAP1/TEAD2 signaling upregulates STIM1 in vemurafenib resistant melanoma cells. 表皮生长因子受体/表皮生长因子受体-YAP1/TEAD2信号传导可上调对维莫非尼耐药的黑色素瘤细胞中的STIM1。

The FEBS journal Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI: 10.1111/febs.17272

Weiyu Bai, Chenghao Yan, Yichen Yang, Lei Sang, Qinggang Hao, Xinyi Yao, Yingru Zhang, Jia Yu, Yifan Wang, Xiaowen Li, Mingyao Meng, Jilong Yang, Junling Shen, Yan Sun, Jianwei Sun

{"title":"EGF/EGFR-YAP1/TEAD2 signaling upregulates STIM1 in vemurafenib resistant melanoma cells.","authors":"Weiyu Bai, Chenghao Yan, Yichen Yang, Lei Sang, Qinggang Hao, Xinyi Yao, Yingru Zhang, Jia Yu, Yifan Wang, Xiaowen Li, Mingyao Meng, Jilong Yang, Junling Shen, Yan Sun, Jianwei Sun","doi":"10.1111/febs.17272","DOIUrl":"10.1111/febs.17272","url":null,"abstract":"Stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum Ca2+ sensor for store-operated calcium entry and is closely associated with carcinogenesis and tumor progression. Previously, we found that STIM1 is upregulated in melanoma cells resistant to the serine/threonine-protein kinase B-raf inhibitor vemurafenib, although the mechanism underlying this upregulation is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR)-Yes-associated protein 1 (YAP1)/TEA domain transcription factor 2 (TEAD2) signaling axis. Vemurafenib resistance can lead to an increase in EGF and EGFR levels, causing activation of the EGFR signaling pathway, which promotes YAP1 nuclear localization to increase the expression of STIM1. Our findings not only reveal the mechanism by which vemurafenib resistance promotes STIM1 upregulation, but also provide a rationale for combined targeting of the EGF/EGFR-YAP1/TEAD2-STIM1 axis to improve the therapeutic efficacy of BRAF inhibitor in melanoma patients.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biochemical and kinetic properties of three indoleamine 2,3-dioxygenases of Aspergillus fumigatus: mechanism of increase in the apparent K_m by ascorbate. 曲霉的三种吲哚胺 2,3 二氧化酶的生物化学和动力学特性：抗坏血酸增加表观 Km 的机理。

The FEBS journal Pub Date : 2024-11-01 Epub Date: 2024-10-07 DOI: 10.1111/febs.17290

Hajime Julie Yuasa

{"title":"Biochemical and kinetic properties of three indoleamine 2,3-dioxygenases of Aspergillus fumigatus: mechanism of increase in the apparent Km by ascorbate.","authors":"Hajime Julie Yuasa","doi":"10.1111/febs.17290","DOIUrl":"10.1111/febs.17290","url":null,"abstract":"Indoleamine 2,3-dioxygenase (IDO) is a monomeric heme enzyme that catalyzes the oxidative cleavage of tryptophan (L-Trp) to form N-formyl-kynurenine. Similar to other heme proteins, IDO only binds to O2 when the heme iron is ferrous (FeII), thereby rendering the enzyme active. Thus, ascorbate (Asc, a reducing agent) and methylene blue (MB, an electron carrier) are commonly added to in vitro IDO assay systems. However, Asc and MB have been recently reported to significantly impact the measurement of the enzymatic parameters of vertebrate IDO. Aspergillus fumigatus is a filamentous fungus and the most common cause of invasive aspergillosis; it has three IDO genes (IDOα, IDOβ, and IDOγ). The FeII-O2 IDOs of A. fumigatus, particularly FeII-O2 IDOγ, have relatively long half-lives in their autoxidation; however, the autoxidation was accelerated by Asc. Similar to vertebrate IDOs, Asc acted as a competitive (or mixed-competitive) inhibitor of the IDOs of A. fumigatus. A positive correlation (in the order of IDOγ > IDOβ > IDOα) was observed between the inhibitory sensitivity of the IDOs to Asc and the facilitation of their autoxidation by Asc. The FeII-O2 IDO can repeat the dioxygenase reaction as long as it reacts with L-Trp; however, substrate-free FeII-O2 IDO is converted into inactive FeIII-IDO by autoxidation. Thus, L-Trp (which keeps the IDO active) competes with Asc (which inactivates IDO by accelerating autoxidation). This is probably why Asc, which is structurally quite different from L-Trp, appears to function as a competitive (or mixed-competitive) inhibitor of IDOs.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142396478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A structural snapshot of the multiple working states of the Mpox virus helicase-primase D5. Mpox 病毒螺旋酶-primase D5 多种工作状态的结构快照。

The FEBS journal Pub Date : 2024-10-29 DOI: 10.1111/febs.17292

Yingying Guo, Renhong Yan

引用次数: 0

Interleukin-11 receptor is an alternative α-receptor for interleukin-6 and the chimeric cytokine IC7. 白细胞介素-11 受体是白细胞介素-6 和嵌合细胞因子 IC7 的另一种 α 受体。

The FEBS journal Pub Date : 2024-10-29 DOI: 10.1111/febs.17309

Hendrik T Weitz, Julia Ettich, Puyan Rafii, Christoph Wittich, Laura Schultz, Nils C Frank, Denise Heise, Matthias Krusche, Juliane Lokau, Christoph Garbers, Kristina Behnke, Doreen M Floss, Harald Kolmar, Jens M Moll, Jürgen Scheller

{"title":"Interleukin-11 receptor is an alternative α-receptor for interleukin-6 and the chimeric cytokine IC7.","authors":"Hendrik T Weitz, Julia Ettich, Puyan Rafii, Christoph Wittich, Laura Schultz, Nils C Frank, Denise Heise, Matthias Krusche, Juliane Lokau, Christoph Garbers, Kristina Behnke, Doreen M Floss, Harald Kolmar, Jens M Moll, Jürgen Scheller","doi":"10.1111/febs.17309","DOIUrl":"https://doi.org/10.1111/febs.17309","url":null,"abstract":"The cytokine interleukin 6 (IL-6) signals via the IL-6 α-receptor (IL-6Rα or IL-6R) in complex with the gp130 β-receptor. Cell type restricted expression of the IL-6R limits the action of IL-6 mainly to hepatocytes and some immune cells. Here, we show that IL-6 also binds to the IL-11 α receptor (IL-11Rα or IL-11R) and induces signaling via IL-11R:gp130 complexes, albeit with a lower affinity compared to IL-11. Antagonistic antibodies directed against IL-11R, but not IL-6R, inhibit IL-6 signaling via IL-11R:gp130 receptor complexes. Notably, IL-11 did not cross-react with IL-6R. IL-11R has also been identified as an alternative α receptor for the CNTF/IL-6-derived chimeric cytokine IC7, which has recently been shown to induce weight loss in mice. Accordingly, the effects of therapeutic monoclonal antibodies against IL-6 or IL-6R, which both block IL-6 signaling, may be slightly different. These findings provide new insights into IL-6 signaling and therefore offer new potential therapeutic intervention options in the future.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and biophysical characterisation of ubiquitin variants that inhibit the ubiquitin conjugating enzyme Ube2d2. 抑制泛素连接酶 Ube2d2 的泛素变体的结构和生物物理特征。

The FEBS journal Pub Date : 2024-10-29 DOI: 10.1111/febs.17311

Jeffery M R B McAlpine, Gene Zhu, Nicholas Pudjihartono, Joan Teyra, Michael J Currie, Zachary D Tillett, Renwick C J Dobson, Sachdev S Sidhu, Catherine L Day, Adam J Middleton

{"title":"Structural and biophysical characterisation of ubiquitin variants that inhibit the ubiquitin conjugating enzyme Ube2d2.","authors":"Jeffery M R B McAlpine, Gene Zhu, Nicholas Pudjihartono, Joan Teyra, Michael J Currie, Zachary D Tillett, Renwick C J Dobson, Sachdev S Sidhu, Catherine L Day, Adam J Middleton","doi":"10.1111/febs.17311","DOIUrl":"https://doi.org/10.1111/febs.17311","url":null,"abstract":"The ubiquitin-conjugating E2 enzymes play a central role in ubiquitin transfer. Disruptions to the ubiquitin system are implicated in multiple diseases, and as a result, molecules that modulate the activity of the ubiquitin system are of interest. E2 enzyme function relies on interactions with partner proteins, and the disruption of these is an effective way to modulate activity. Here, we report the discovery of ubiquitin variants (UbVs) that inhibit the E2 enzyme, Ube2d2 (UbcH5b). The six UbVs identified inhibit ubiquitin chain building, and the structural and biophysical characterisation of two of these demonstrate they bind to Ube2d2 with low micromolar affinity and high specificity. Both characterised UbVs bind at a site that overlaps with E1 binding, while the more inhibitory UbV has an additional binding site that blocks a critical non-covalent ubiquitin-binding site on the E2 enzyme. The discovery of novel protein-based ubiquitin derivatives that inhibit protein-protein interactions is an important step towards discovering small molecules that inhibit the activity of E2 enzymes. Furthermore, the specificity of the UbVs within the Ube2d family suggests that it may be possible to develop tools to selectively inhibit highly related E2 enzymes.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The small molecule ZPD-2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein. 小分子 ZPD-2 可抑制 C 端截短的α-突触核蛋白的聚集和种子聚合。

The FEBS journal Pub Date : 2024-10-27 DOI: 10.1111/febs.17310

Samuel Peña-Díaz, Salvador Ventura

引用次数: 0

The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis. IL-11信号复合体的结构使人们能够深入了解与颅骨发育不良有关的受体变异。

The FEBS journal Pub Date : 2024-10-27 DOI: 10.1111/febs.17307

Darlene D Sentosa, Riley D Metcalfe, Natalie A Sims, Tracy L Putoczki, Michael D W Griffin

{"title":"The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis.","authors":"Darlene D Sentosa, Riley D Metcalfe, Natalie A Sims, Tracy L Putoczki, Michael D W Griffin","doi":"10.1111/febs.17307","DOIUrl":"https://doi.org/10.1111/febs.17307","url":null,"abstract":"Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor α subunit (IL-11Rα) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11Rα are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A ZO-2 scaffolding mechanism regulates the Hippo signalling pathway. ZO-2支架机制调节Hippo信号通路。

The FEBS journal Pub Date : 2024-10-27 DOI: 10.1111/febs.17304

Olivia Xuan Liu, Lester Bocheng Lin, Soumya Bunk, Tiweng Chew, Selwin K Wu, Fumio Motegi, Boon Chuan Low

引用次数: 0

Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality. 配体结合的化学计量以及 C 端赖氨酸在结核分枝杆菌和人类 GAPDH 多功能性中的作用。

The FEBS journal Pub Date : 2024-10-22 DOI: 10.1111/febs.17298

Ajay Kumar, Rajender Kumar, Vishant Mahendra Boradia, Himanshu Malhotra, Adarsh Kumar, Sriraj Seth, Prabha Garg, Subramanian Karthikeyan, Manoj Raje, Chaaya Iyengar Raje

{"title":"Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality.","authors":"Ajay Kumar, Rajender Kumar, Vishant Mahendra Boradia, Himanshu Malhotra, Adarsh Kumar, Sriraj Seth, Prabha Garg, Subramanian Karthikeyan, Manoj Raje, Chaaya Iyengar Raje","doi":"10.1111/febs.17298","DOIUrl":"https://doi.org/10.1111/febs.17298","url":null,"abstract":"Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH; EC1.2.1.12) has several functions in Mycobacterium tuberculosis (Mtb) and the human host. Apart from its role in glycolysis, it serves both as a cell surface and a secreted receptor for plasmin(ogen) (Plg/Plm), transferrin (Tf), and lactoferrin (Lf). Plg sequestration by Mtb GAPDH facilitates bacterial adhesion and tissue invasion, while an equivalent interaction with host GAPDH regulates immune cell migration. In both, host and microbe, internalization of Tf/Lf-GAPDH complexes serves as a route for iron acquisition. To date, the structure of Mtb GAPDH or the residues involved in these moonlighting interactions have not been identified. This study provides the first known X-ray crystal structure of Mtb GAPDH. Through further mutagenesis and functional assays, we found that the C-terminal lysines of Mtb and human GAPDH affect enzyme activity and ligand binding. We also establish the stoichiometry of Plg, Tf and Lf interactions with the GAPDH tetramer. Lastly, molecular simulation studies reveal the interactions of the C-terminal lysine residues.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0