The FEBS journal最新文献_第2页

Lipid regulation of adenylyl cyclase Rv1625c from Mycobacterium tuberculosis by its membrane-domain receptor. 结核分枝杆菌腺苷酸环化酶Rv1625c膜结构域受体的脂质调控

The FEBS journal Pub Date : 2025-06-01 DOI: 10.1111/febs.70148

Anita Charlotte Friderun Schultz, Marius Landau, Andrei N Lupas, Joachim Erdmann Schultz

{"title":"Lipid regulation of adenylyl cyclase Rv1625c from Mycobacterium tuberculosis by its membrane-domain receptor.","authors":"Anita Charlotte Friderun Schultz, Marius Landau, Andrei N Lupas, Joachim Erdmann Schultz","doi":"10.1111/febs.70148","DOIUrl":"https://doi.org/10.1111/febs.70148","url":null,"abstract":"The regulation of mammalian adenylyl cyclases by G-protein-coupled receptors and the Gsα subunit of trimeric G-proteins has been extensively studied, whereas little is known about the regulation of their closely related bacterial cyclases. Here, we focused on the regulation of the adenylyl cyclase Rv1625c from Mycobacterium tuberculosis H37Rv. Rv1625c is a progenitor of mammalian congeners. Exclusively C18-mono-unsaturated fatty acids, such as the cis- and trans-isoforms of oleic and vaccenic acids, inhibited the Rv1625c holoenzyme with IC50 concentrations around 10 μm. The saturated C18 fatty acid stearic acid was inactive. A soluble Rv1625c construct, which lacked the membrane domain, was not affected by the mono-unsaturated C18 fatty acids, i.e., the inhibition required the presence of the membrane domain, indicating a receptor-ligand interaction. Surprisingly, fatty acid inhibition of Rv1625c was strictly dependent on magnesium ions (Mg2+) as a divalent cation for the substrate adenosine triphosphate (ATP). Although manganese ion (Mn2+)-ATP as a substrate greatly increased enzyme activity, Mn2+ appeared to block intramolecular signal transduction from the membranous receptor domain to the catalytic effector domain. In summary, the results bolster the proposal that adenylyl cyclase regulation by fatty acids is an evolutionarily conserved signaling mode present in bacteria as well as in mammals.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201234","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

In vivo and in silico models of Drosophila for Parkinson's disease. 帕金森病的果蝇体内和计算机模型。

The FEBS journal Pub Date : 2025-06-01 DOI: 10.1111/febs.70140

Müberra Fatma Cesur, Rachel Strazdins, Souvarish Sarkar, Tunahan Çakır

{"title":"In vivo and in silico models of Drosophila for Parkinson's disease.","authors":"Müberra Fatma Cesur, Rachel Strazdins, Souvarish Sarkar, Tunahan Çakır","doi":"10.1111/febs.70140","DOIUrl":"https://doi.org/10.1111/febs.70140","url":null,"abstract":"The fruit fly Drosophila melanogaster has emerged as an important model organism to shed light on neurodegeneration. Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, the cause of which is still mostly unclear. The long-term use of available PD drugs may have major side effects, and they only target the symptoms without providing any effective cure for the disease. Therefore, in vivo and in silico approaches are extensively used to model PD-like phenotypes in Drosophila and investigate cellular alterations underlying PD pathogenesis. In vivo models are particularly crucial to provide insight into the PD-related molecular processes. It has been a preferred approach to investigate these models by collecting omics datasets, which can be further analysed using in silico modeling such as genome-scale metabolic models and artificial intelligence applications. This review aims to summarise in vivo and in silico modeling studies in the literature to illustrate the potential of the Drosophila in the characterisation of PD-related biological mechanisms towards providing early biomarkers and novel treatment options for PD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201233","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

PINK1/Parkin-based live-cell quantitative FRET imaging for mitophagy drug screening. 基于PINK1/帕金森的活细胞定量FRET成像用于有丝分裂药物筛选。

The FEBS journal Pub Date : 2025-06-01 DOI: 10.1111/febs.70146

Beini Sun, Kangrong Deng, Qialing Huang, Lin Cheng, Wei Yao, Zhirui Wu, Xiaoping Wang, Ming Dong, Tongsheng Chen

{"title":"PINK1/Parkin-based live-cell quantitative FRET imaging for mitophagy drug screening.","authors":"Beini Sun, Kangrong Deng, Qialing Huang, Lin Cheng, Wei Yao, Zhirui Wu, Xiaoping Wang, Ming Dong, Tongsheng Chen","doi":"10.1111/febs.70146","DOIUrl":"https://doi.org/10.1111/febs.70146","url":null,"abstract":"PINK1 (PTEN-induced kinase 1) and Parkin (parkin RBR E3 ubiquitin protein) ligase are important regulators for cells to maintain mitochondrial number and functional homeostasis. Here, we established a PINK1/Parkin-based mitophagy drug evaluation method using quantitative Förster resonance energy transfer (FRET) imaging in living cells. A stable model of carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced mitophagy was established, verified by increased colocalization of mitochondria with LC3 aggregates, decreased mitochondrial membrane potential (MMP), and increased intracellular reactive oxygen species (ROS) level. Next, by silencing PINK1 and overexpressing LC3 proteins in MCF-7 cells, it was verified that PINK1 and Parkin significantly promoted CCCP-induced mitophagy, in which CCCP promoted the direct interaction of PINK1 and Parkin. Quantitative FRET imaging analysis for the cells coexpressing CFP-PINK1 and YFP-Parkin was used to assess the action of five drugs [3-methyladenine (3-MA), CCCP, doxorubicin hydrochloride (DOX), metformin (Met), resveratrol (RSV)] on the interaction between PINK1 and Parkin. After 6 h of treatment with these drugs, the CCCP, DOX, Met, and RSV groups showed significantly higher maximum donor-centric FRET efficiency (EDmax) than the control group, suggesting that these four drugs promoted the direct interaction between PINK1 and Parkin. While the 3-MA group showed similar EDmax to the control group, suggesting that 3-MA did not promote direct interaction between PINK1 and Parkin. We also performed these experiments in HeLa cells and obtained the same results, further demonstrating that the PINK1/Parkin-based quantitative FRET drug screening method is a potential tool for mitophagy drug screening in living cells.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201169","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

Gα_s-specific structural elements attenuate interactions with regulator of G protein signaling (RGS) proteins. Gαs特异性结构元件减弱与G蛋白信号（RGS）蛋白的相互作用。

The FEBS journal Pub Date : 2025-05-28 DOI: 10.1111/febs.70149

Sabreen Higazy-Mreih, Meirav Avital-Shacham, Christian LeGouill, Michel Bouvier, Mickey Kosloff

{"title":"Gαs-specific structural elements attenuate interactions with regulator of G protein signaling (RGS) proteins.","authors":"Sabreen Higazy-Mreih, Meirav Avital-Shacham, Christian LeGouill, Michel Bouvier, Mickey Kosloff","doi":"10.1111/febs.70149","DOIUrl":"https://doi.org/10.1111/febs.70149","url":null,"abstract":"Heterotrimeric (αβγ) G proteins are molecular switches that are activated by G protein-coupled receptors (GPCRs) and regulate numerous intracellular signaling cascades. Most active Gα subunits are inactivated by regulators of G protein signaling (RGS) proteins, which determine the duration of G protein-mediated signaling by accelerating the catalytic turn-off of the Gα subunit. However, the G protein Gαs does not interact with known RGS proteins. To understand the molecular basis for this divergent phenomenon, we combined a comparative structural analysis of experimental and modeled structures with functional biochemical assays. This analysis showed that Gαs contains unique structural elements in both the helical and the GTPase domains. Modeling suggested that helical domain insertions, which were missing in experimental structures, might project toward the interface with RGS proteins. Alternatively, residues in the Gαs GTPase domain might lead to direct interference with RGS binding. Mutagenesis of Gαs and measurements of RGS GTPase-activating protein (GAP) activity showed that three residues in the Gαs GTPase domain are both necessary and sufficient to prevent Gαs inactivation by RGSs. Indeed, substitution of all three Gαs residues with the corresponding residues from Gαi1 enabled efficient inactivation by RGS proteins. These results shed new light on the mechanistic bases for G protein specificity toward RGS proteins.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176402","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

Cadherin-6 controls neuronal migration during mouse neocortical development via an integrin-mediated pathway. 钙粘蛋白-6通过整合素介导的途径控制小鼠新皮质发育过程中的神经元迁移。

The FEBS journal Pub Date : 2025-05-28 DOI: 10.1111/febs.70150

Yuki Hirota, Rikaho Saito, Takao Honda, Hitomi Sano, Mayuko Hotta, Yukiko U Inoue, Takayoshi Inoue, Kazunori Nakajima

{"title":"Cadherin-6 controls neuronal migration during mouse neocortical development via an integrin-mediated pathway.","authors":"Yuki Hirota, Rikaho Saito, Takao Honda, Hitomi Sano, Mayuko Hotta, Yukiko U Inoue, Takayoshi Inoue, Kazunori Nakajima","doi":"10.1111/febs.70150","DOIUrl":"https://doi.org/10.1111/febs.70150","url":null,"abstract":"During neocortical development, neuronal migration is highly regulated by multiple signaling cascades, including the cell adhesion molecules. Cadherin-6 (CDH6), an unusual cadherin molecule containing an RGD integrin-binding motif, has multiple functions in the developing nervous system, but whether it contributes to neuronal migration and positioning during neocortical development remains unknown. Here, we investigated the role of CDH6 in the developing cerebral cortex. Cdh6 knockdown (KD) using in utero electroporation revealed that CDH6 inhibition caused impaired radial migration and abnormal positioning of neurons. Time-lapse imaging analysis revealed that CDH6 is important for proper neuronal motility. Mechanistically, we show that CDH6 promotes the activation of integrin β1 on migrating neurons. The defect in neuronal migration caused by Cdh6 KD was rescued by moderate overexpression of integrin β1 and a KD-resistant form of wild-type CDH6, but not by CDH6 with a mutated RGD motif. These results suggest that CDH6 is required for cortical excitatory neurons to migrate radially by controlling integrin-mediated cell motility.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176401","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

Anions and citrate inhibit LsAA9A, a lytic polysaccharide monooxygenase (LPMO). 阴离子和柠檬酸抑制多糖单加氧酶LsAA9A。

The FEBS journal Pub Date : 2025-05-27 DOI: 10.1111/febs.70138

Valerio Di Domenico, Yusuf Theibich, Søren Brander, Jean-Guy Berrin, Katja S Johansen, Kristian E H Frandsen, Leila Lo Leggio

{"title":"Anions and citrate inhibit LsAA9A, a lytic polysaccharide monooxygenase (LPMO).","authors":"Valerio Di Domenico, Yusuf Theibich, Søren Brander, Jean-Guy Berrin, Katja S Johansen, Kristian E H Frandsen, Leila Lo Leggio","doi":"10.1111/febs.70138","DOIUrl":"https://doi.org/10.1111/febs.70138","url":null,"abstract":"Lytic polysaccharide monooxygenases (LPMOs) are oxidative enzymes that break the glycosidic linkage in recalcitrant polysaccharides such as cellulose and chitin. The LPMO LsAA9A (AA9 family lytic polysaccharide monooxygenase A) from the basidiomycete fungus Lentinus similis is biochemically and structurally well characterized, with crystallographic complexes with oligosaccharides having been obtained. Chloride ions from the crystallization solution are known to bind to the LsAA9A-substrate complex in crystals at the copper equatorial coordinating position, where activation of the co-substrate oxygen species is expected. An investigation of the effect of high concentration salts on LsAA9A activity showed that salts containing chloride and other halide anions, except for fluoride, had a clear inhibitory effect on the activity at concentrations > 100 mm, although chloride ions are known to increase the LPMO affinity for oligosaccharide binding. Surprisingly, LsAA9A crystals can be transferred for short times to considerably different chemical environments, allowing crystallographic analysis at reduced chloride concentrations. Unfortunately, these washing steps do not eliminate the chloride binding at the copper equatorial coordinating position. Furthermore, we observed that citrate buffer, also present, bound under these changed chemical conditions at the copper active site. This interaction completely blocks access to the oligosaccharide substrate and is additionally supported here by citrate inhibition of LsAA9A activities against azurine cross-linked hydroxyethylcellulose (AZCL-HEC), tamarind xyloglucan, and cellopentaose. The conclusions from our study indicate that citrate should be absolutely avoided in LPMO research, not only because of possible abstraction of copper ions from the LPMO active site but also because it might directly compete with binding of LPMOs to their target substrates.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153168","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

TENT5C functions as a corepressor in the ligand-bound glucocorticoid receptor and estrogen receptor α complexes. TENT5C在配体结合的糖皮质激素受体和雌激素受体α复合物中起辅抑制作用。

The FEBS journal Pub Date : 2025-05-27 DOI: 10.1111/febs.70137

Yin Li, Lalith Perera, Rebecca S He, Marine Baptissart, Robert M Petrovich, Marcos Morgan

{"title":"TENT5C functions as a corepressor in the ligand-bound glucocorticoid receptor and estrogen receptor α complexes.","authors":"Yin Li, Lalith Perera, Rebecca S He, Marine Baptissart, Robert M Petrovich, Marcos Morgan","doi":"10.1111/febs.70137","DOIUrl":"https://doi.org/10.1111/febs.70137","url":null,"abstract":"Terminal nucleotidyltransferase 5C (TENT5C) is a noncanonical poly(A) polymerase that promotes cancer suppression. TENT5C has been proposed to mediate the susceptibility of multiple myeloma to treatment with dexamethasone, a steroid hormone analog that binds to the glucocorticoid receptor (GR). However, the relationship between TENT5C and nuclear receptor (NR) signaling remains unclear. In this study, we investigate the regulatory role of TENT5C in the GR and estrogen receptor α (ERα) ligand complexes. We find that TENT5C acts as a corepressor of both GR and ERα. Molecular dynamics simulations indicate that the third TENT5C LXXLL motif directly interacts with ERα, but not GR. The physical interaction of TENT5C and ERα is supported by co-immunoprecipitation assays. Reporter assays show that mutations to the third TENT5C LXXLL motif disrupt TENT5C-mediated repression of ERα but do not affect the repression of the GR complex. In addition, the disruption of TENT5C poly(A) polymerase activity does not appear to affect TENT5C repression of ERα in the cell lines studied. Taken together, our findings highlight a role of TENT5C as an NR corepressor, differentially modulating GR- and ERα-induced transcriptional activity.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153181","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

Breaking the one-site myth: the multifaceted world of proton sensing in GPCRs. 打破单位点神话：GPCRs中质子传感的多面世界。

The FEBS journal Pub Date : 2025-05-26 DOI: 10.1111/febs.70145

Mahek Agrawal, Swapnil Kumar Singh, Mithu Baidya, Punita Kumari

{"title":"Breaking the one-site myth: the multifaceted world of proton sensing in GPCRs.","authors":"Mahek Agrawal, Swapnil Kumar Singh, Mithu Baidya, Punita Kumari","doi":"10.1111/febs.70145","DOIUrl":"https://doi.org/10.1111/febs.70145","url":null,"abstract":"Proton-sensing GPCRs detect extracellular acidification and play a pivotal role in maintaining pH homeostasis, influencing processes such as inflammation, cancer progression, and neuropathic pain. While initially believed to rely solely on histidine protonation for activation, emerging evidence suggests that acidic triads, beyond histidine residues, are crucial for proton sensing. Variations in histidine distribution and sequence composition among these receptors point to distinct activation mechanisms within the proton-sensing GPCR family. This Viewpoint consolidates findings from previously published studies to explore the structural and molecular intricacies of proton recognition, receptor activation, and downstream signaling in proton-sensing GPCRs. By integrating insights from molecular dynamics simulations, evolutionary analysis, structural studies, and functional assays, we highlight the complex and multifaceted nature of GPCRs in proton sensing. Collectively, these studies reveal a previously unrecognized network of critical residues and activation sites, reshaping our understanding of GPCR function. Beyond structural and mechanistic insights, this compilation of findings offers new perspectives on targeting proton-sensing pathways for therapeutic intervention in various diseases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153171","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

Probing a salt-induced conformational switch in β₂-microglobulin under low pH conditions. 在低pH条件下探测盐诱导的β2微球蛋白构象开关。

The FEBS journal Pub Date : 2025-05-26 DOI: 10.1111/febs.70142

Khushboo Rani, Bharat Gurnani, Neha Jain

{"title":"Probing a salt-induced conformational switch in β2-microglobulin under low pH conditions.","authors":"Khushboo Rani, Bharat Gurnani, Neha Jain","doi":"10.1111/febs.70142","DOIUrl":"https://doi.org/10.1111/febs.70142","url":null,"abstract":"Self-assembly of proteins and peptides into amyloid fibrils is an active field of research due to its connection with debilitating human ailments such as Parkinson's disease, dialysis-related amyloidosis (DRA), and type II diabetes. In most disease conditions, amyloid formation proceeds via distinct on-pathway conformers such as oligomers and protofibrils. However, the detailed mechanism by which monomers transform into different species and contribute to disease progression remains an area of intense research. Isolating and characterizing distinct conformers are pertinent to understanding disease initiation and progression. One such ailment is DRA, where an amyloidogenic protein, β2-microglobulin (β2m), undergoes a profound conformational switch to adopt an amyloid fold. β2m amyloids accumulate in tissues such as joints and kidneys, causing tissue damage and dysfunction. Soluble β2m oligomers are considered more toxic than amyloids due to impaired cellular processes, resulting in cell death. In the present study, we have identified and characterized three stages of β2m aggregation, namely, oligomers, protofibrils, and fibrils, while varying salt concentrations and agitation under low pH conditions. Our kinetic results indicate that β2m oligomers and protofibrils follow a nucleation-independent pathway, whereas amyloids are formed through the classical nucleation process. Further, we implemented microscopic techniques and biochemical assays to verify the formation and stability of distinct conformers. We believe these findings provide insights into the process of amyloid formation, which may help us to understand the initiation of the disease at an early stage.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153178","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 Rab25-ADAMTS5 axis as a previously undescribed mechanism for sensing tumor microenvironment complexity. Rab25-ADAMTS5轴是先前描述的感知肿瘤微环境复杂性的机制。

The FEBS journal Pub Date : 2025-05-23 DOI: 10.1111/febs.70147

François Tyckaert, Francesco Baschieri

引用次数: 0