The FEBS journal最新文献_第3页

Highly divergent apicomplexan cytoskeletons provide additional models for actin biology. 高度分化的顶复合体细胞骨架为肌动蛋白生物学提供了额外的模型。

IF 4.2

The FEBS journal Pub Date : 2025-09-13 DOI: 10.1111/febs.70263

Yukino Kobayashi, Ross G Douglas

引用次数: 0

SET domain containing 3 (SETD3) interacts with bromodomain-containing protein 2 (BRD2) and coordinates its chromatin association in mouse embryonic stem cells. 在小鼠胚胎干细胞中，SET结构域3 （SETD3）与含溴结构域蛋白2 （BRD2）相互作用并协调其染色质关联。

IF 4.2

The FEBS journal Pub Date : 2025-09-13 DOI: 10.1111/febs.70261

Dersu Sezginmert, Gozde Guven, Ceren Alganatay, Deniz Ak, Nihal Terzi Cizmecioglu

{"title":"SET domain containing 3 (SETD3) interacts with bromodomain-containing protein 2 (BRD2) and coordinates its chromatin association in mouse embryonic stem cells.","authors":"Dersu Sezginmert, Gozde Guven, Ceren Alganatay, Deniz Ak, Nihal Terzi Cizmecioglu","doi":"10.1111/febs.70261","DOIUrl":"https://doi.org/10.1111/febs.70261","url":null,"abstract":"Regulation of cell fate decisions during early embryonic development requires precise temporal and spatial control. The embryonic stem cell (ESC) transcription factor network maintains a delicate balance between self-renewal and differentiation by suppressing lineage-specific transcription while upregulating pluripotency factors. Our previous studies highlighted a critical role for the SET domain-containing protein actin-histidine N-methyltransferase (SETD3) in endoderm differentiation of mouse embryonic stem cells (mESCs). However, its specific functions within the nuclear context remained poorly understood. In this study, we used mass spectrometry to identify nuclear protein partners of SETD3. Our findings revealed that SETD3 interacts with the transcription factor CP2-like protein 1 (TFCP2L1; a pluripotency transcription factor) and bromodomain-containing protein 2 (BRD2) in the nucleus. Notably, our study highlights an essential role of SETD3 in the recruitment of BRD2 to chromatin in mESCs. Through domain deletions and proximity ligation assays, we established that this interaction is dependent on the RSB domain of SETD3 and potentially the BD2 domain of BRD2. The absence of SETD3 led to considerable alterations in the chromatin environment and a significant reduction in BRD2 recruitment, resulting in transcriptional changes. Our findings highlight the significant role of SETD3-dependent BRD2 recruitment in regulating chromatin dynamics and transcriptional outcomes in mESCs, enhancing our understanding of its role in ESC pluripotency exit and lineage commitment.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058858","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

Activator of apoptosis harakiri (HRK) localisation at mitochondria alters mitochondrial morphology independently of other BCL-2 proteins. 凋亡激活因子harakiri （HRK）定位于线粒体改变线粒体形态独立于其他BCL-2蛋白。

IF 4.2

The FEBS journal Pub Date : 2025-09-12 DOI: 10.1111/febs.70255

Louise E King, Lukas Faber, Ana J García-Sáez

{"title":"Activator of apoptosis harakiri (HRK) localisation at mitochondria alters mitochondrial morphology independently of other BCL-2 proteins.","authors":"Louise E King, Lukas Faber, Ana J García-Sáez","doi":"10.1111/febs.70255","DOIUrl":"https://doi.org/10.1111/febs.70255","url":null,"abstract":"The activator of apoptosis harakiri (HRK) is a pro-apoptotic BCL-2 homology 3 (BH3)-only protein of the apoptosis regulator Bcl-2 (BCL-2) family that is mainly expressed in neuronal and haematopoietic tissues. How specific HRK protein domains contribute to its pro-apoptotic function, and what other non-apoptotic roles HRK performs within cells, remain poorly understood. Here, we evaluated the apoptosis sensitivity, and mitochondrial shape and function of HCT116 human colorectal cells lacking all BH3-only proteins as well as all relevant BCL-2 proteins. By reconstituting individual BH3-only proteins on this genetic background, we observed that HRK induces apoptosis in a manner dependent on its BH3 domain, and the presence of the apoptosis regulator BAX and BCL-2 homologous antagonist/killer (BAK), but independent of its transmembrane domain. Intriguingly, HRK also causes mitochondrial aggregation without altering cristae structure or respiration. Although the BH3 domain is not required for mitochondrial reorganisation, we found that the transmembrane domain requires additional upstream amino acids for HRK mitochondrial localisation and reorganisation. These observations uncover a previously unknown role of HRK in modulating mitochondrial morphology that is independent of its BH3 domain and pro-death function.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056479","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

DNA damage in mitosis: SOD1 delays anaphase onset. 有丝分裂中的DNA损伤：SOD1延迟后期开始。

IF 4.2

The FEBS journal Pub Date : 2025-09-12 DOI: 10.1111/febs.70264

George Zachos

引用次数: 0

Structural analysis of the NifL-NifA complex reveals the molecular basis of anti-activation of nitrogen fixation gene expression in Azotobacter vinelandii. NifL-NifA复合物的结构分析揭示了固氮基因表达抗活化的分子基础。

IF 4.2

The FEBS journal Pub Date : 2025-09-07 DOI: 10.1111/febs.70253

Marcelo Bueno Batista, Jake Richardson, Michael W Webster, Dmitry Ghilarov, John W Peters, David M Lawson, Ray Dixon

{"title":"Structural analysis of the NifL-NifA complex reveals the molecular basis of anti-activation of nitrogen fixation gene expression in Azotobacter vinelandii.","authors":"Marcelo Bueno Batista, Jake Richardson, Michael W Webster, Dmitry Ghilarov, John W Peters, David M Lawson, Ray Dixon","doi":"10.1111/febs.70253","DOIUrl":"https://doi.org/10.1111/febs.70253","url":null,"abstract":"Understanding the molecular basis of regulated nitrogen (N2) fixation is essential for engineering N2-fixing bacteria that fulfill the demand of crop plants for fixed nitrogen, reducing our reliance on synthetic nitrogen fertilizers. In Azotobacter vinelandii and many other members of Proteobacteria, the two-component system comprising the anti-activator protein (NifL) and the Nif-specific transcriptional activator (NifA)controls the expression of nif genes, encoding the nitrogen fixation machinery. The NifL-NifA system evolved the ability to integrate several environmental cues, such as oxygen, nitrogen, and carbon availability. The nitrogen fixation machinery is thereby only activated under strictly favorable conditions, enabling diazotrophs to thrive in competitive environments. While genetic and biochemical studies have enlightened our understanding of how NifL represses NifA, the molecular basis of NifA sequestration by NifL depends on structural information on their interaction. Here, we present mechanistic insights into how nitrogen fixation is regulated by combining biochemical and genetic approaches with a low-resolution cryo-electron microscopy (cryo-EM) map of the oxidized NifL-NifA complex. Our findings define the interaction surface between NifL and NifA and reveal how this interaction can be manipulated to generate bacterial strains with increased nitrogen fixation rates able to secrete surplus nitrogen outside the cell, a crucial step in engineering improved nitrogen delivery to crop plants.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017091","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

Neutron diffraction reveals protonation states in pyridoxal-5'-phosphate-free and glycine external aldimine-bound serine hydroxymethyltransferase. 中子衍射揭示了吡哆醛-5'-无磷酸和甘氨酸外醛缩结合丝氨酸羟甲基转移酶的质子化状态。

IF 4.2

The FEBS journal Pub Date : 2025-09-07 DOI: 10.1111/febs.70260

Victoria N Drago, Matthew P Blakeley, Robert S Phillips, Andrey Kovalevsky

{"title":"Neutron diffraction reveals protonation states in pyridoxal-5'-phosphate-free and glycine external aldimine-bound serine hydroxymethyltransferase.","authors":"Victoria N Drago, Matthew P Blakeley, Robert S Phillips, Andrey Kovalevsky","doi":"10.1111/febs.70260","DOIUrl":"https://doi.org/10.1111/febs.70260","url":null,"abstract":"Serine hydroxymethyltransferase (SHMT) is a critical enzyme in the one-carbon (1C) metabolism pathway catalyzing the reversible conversion of L-Ser into Gly and concurrent transfer of 1C unit to tetrahydrofolate (THF) to give 5,10-methylene-THF (5,10-MTHF), which is used in the downstream syntheses of biomolecules critical for cell proliferation. The cellular 1C metabolism is hijacked by many cancer types to support cancer cell proliferation, making SHMT a promising target for the design and development of novel small-molecule antimetabolite chemotherapies. To advance structure-assisted drug design, knowledge of SHMT catalysis is crucial, but can only be fully realized when the atomic details of each reaction step governed by the acid-base catalysis are elucidated by visualizing active site hydrogen atoms. Here, we used room-temperature neutron crystallography to directly determine protonation states in Thermus thermophilus SHMT (TthSHMT), capturing protomer A in the apo form lacking the coenzyme pyridoxal 5'-phosphate (PLP), and protomer B as a ternary complex with PLP-Gly-external aldimine and (6S)-5-methyltetrahydrofolate (5MTHF). We observed protonation of the Schiff base nitrogen in PLP-Gly and neutrality of the catalytic Lys226 side chain in the ternary complex, whereas Lys226 is protonated and positively charged in the apo-active site. Furthermore, we obtained an X-ray structure of TthSHMT in complex with the substrate THF, which binds identically as 5MTHF at the peripheral binding site. The unique structural and functional information provided by neutron crystallography, in combination with X-ray structures, can be employed in the rational design of SHMT inhibitors.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017027","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

Mechanism for reactivation of inactivated holoenzymes of coenzyme B₁₂-dependent ethanolamine ammonia-lyase by the reactivating chaperone EutA. 辅酶b12依赖性乙醇胺解氨酶失活全酶被再激活的机制

IF 4.2

The FEBS journal Pub Date : 2025-09-07 DOI: 10.1111/febs.70254

Naoki Hieda, Reiko Bando, Keisuke Maeda, Koichi Mori, Tetsuo Toraya

{"title":"Mechanism for reactivation of inactivated holoenzymes of coenzyme B12-dependent ethanolamine ammonia-lyase by the reactivating chaperone EutA.","authors":"Naoki Hieda, Reiko Bando, Keisuke Maeda, Koichi Mori, Tetsuo Toraya","doi":"10.1111/febs.70254","DOIUrl":"https://doi.org/10.1111/febs.70254","url":null,"abstract":"Adenosylcobalamin-dependent ethanolamine ammonia-lyase (EAL) undergoes irreversible inactivation when incubated in the absence of substrate or in the presence of certain substrates or pseudosubstrates. We have previously identified Escherichia coli EutA as an EAL-reactivase (or reactivating factor). Herein, untagged and tagged EutAs were purified to homogeneity. It showed a tendency to form multimers, but its monomer was mainly responsible for reactivation. It showed extremely low but distinct ATPase activity. In the presence of ATP, Mg2+, and free adenosylcobalamin, EutA reactivated holoEALs that had been inactivated in the absence of substrate or suicidally inactivated by 2-aminopropanol, ethylene glycol, or glycolaldehyde. It also activated inactive complexes of EAL with inactive cobalamins, such as cyanocobalamin, hydroxocobalamin, and methylcobalamin, but not the complex with adeninylpentylcobalamin. EutA-mediated cofactor exchange by facilitating the removal of damaged cofactors in the presence of ATP and Mg2+. Here, we postulate a mechanism of action of EutA, which is similar to that of diol dehydratase-reactivase (DD-R). However, contrary to DD-R, its ATP- or 5'-adenylyl imidodiphosphate (AMP-PNP)-bound and ADP-bound forms were suggested to be high-affinity and low-affinity forms for EAL, respectively.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017036","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 structural, functional, and diagnostic significance of NINJ1 in ferroptosis-related diseases. nin1在嗜铁相关疾病中的结构、功能和诊断意义。

IF 4.2

The FEBS journal Pub Date : 2025-09-05 DOI: 10.1111/febs.70258

Zi-Yao Wang, Jing-Wen Zheng, Ping-Yi Tang, Ling Zhu, Jing Ye, Lihong Wan

引用次数: 0

Modifying inhibitor specificity for homologous enzymes by machine learning. 通过机器学习修饰抑制剂对同源酶的特异性。

IF 4.2

The FEBS journal Pub Date : 2025-09-05 DOI: 10.1111/febs.70249

Dor S Gozlan, Reut Meiri, Gili Shapira, Matt Coban, Evette S Radisky, Yaron Orenstein, Niv Papo

{"title":"Modifying inhibitor specificity for homologous enzymes by machine learning.","authors":"Dor S Gozlan, Reut Meiri, Gili Shapira, Matt Coban, Evette S Radisky, Yaron Orenstein, Niv Papo","doi":"10.1111/febs.70249","DOIUrl":"https://doi.org/10.1111/febs.70249","url":null,"abstract":"Selective inhibitors are essential for targeted therapeutics and for probing enzyme functions in various biological systems. The two main challenges in identifying such protein-based inhibitors lie in the extensive experimental effort required, including the generation of large libraries, and in tailoring the selectivity of inhibitors to enzymes with homologous structures. To address these challenges, machine learning (ML) is being used to improve protein design by training on targeted libraries and identifying key interface mutations that enhance affinity and specificity. However, such ML-based methods are limited by inaccurate energy calculations and difficulties in predicting the structural impacts of multiple mutations. Here, we present an ML-based method that leverages HTS data to streamline the design of selective protease inhibitors. To demonstrate its utility, we applied our new method to find inhibitors of matrix metalloproteinases (MMPs), a family of homologous proteases involved in both physiological and pathological processes. By training ML models on binding data for three MMPs (MMP-1, MMP-3, and MMP-9), we successfully designed a novel N-TIMP2 variant with a differential specificity profile, namely, high affinity for MMP-9, moderate affinity for MMP-3, and low affinity for MMP-1. Our experimental validation showed that this novel variant exhibited a significant specificity shift and enhanced selectivity compared with wild-type N-TIMP2. Through molecular modeling and energy minimization, we obtained structural insights into the variant's enhanced selectivity. Our findings highlight the power of ML-based methods to reduce experimental workloads, facilitate the rational design of selective inhibitors, and advance the understanding of specific inhibitor-enzyme interactions in homologous enzyme systems.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006984","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

PU.1 and TGF-β signaling activate the cell-surface expression of CD103 in mast cells and dendritic cells: opposite roles of GATA2 in the expression of mucosal mast cell genes. PU.1和TGF-β信号激活肥大细胞和树突状细胞中CD103的细胞表面表达：GATA2在粘膜肥大细胞基因表达中的作用相反。

IF 4.2

The FEBS journal Pub Date : 2025-09-04 DOI: 10.1111/febs.70252

Kenta Ishii, Kazuki Nagata, Niya Yamashita, Yuki Yamazaki, Yuta Akimoto, Weiting Zhao, Mariko Inoue, Naoto Ito, Kazumi Kasakura, Chiharu Nishiyama

{"title":"PU.1 and TGF-β signaling activate the cell-surface expression of CD103 in mast cells and dendritic cells: opposite roles of GATA2 in the expression of mucosal mast cell genes.","authors":"Kenta Ishii, Kazuki Nagata, Niya Yamashita, Yuki Yamazaki, Yuta Akimoto, Weiting Zhao, Mariko Inoue, Naoto Ito, Kazumi Kasakura, Chiharu Nishiyama","doi":"10.1111/febs.70252","DOIUrl":"https://doi.org/10.1111/febs.70252","url":null,"abstract":"Mucosal mast cells (MMCs) are distinguished from connective tissue mast cells (MCs) by the specific cell-surface expression of integrin CD103 (also known as integrin αE/β7; αE is encoded by Itgae) and mast cell protease 1 and 2 (Mcpt1 and Mcpt2, respectively). Although the expression of the Mcpt1 and Mcpt2 genes is cooperatively regulated by the transcription factor GATA-binding protein 2 (GATA2) and transforming growth factor beta (TGF-β) signaling in MMCs, the transcriptional mechanism of the cell-surface expression of CD103 remains unknown. We herein found that surface CD103 and Itgae mRNA levels were significantly increased by the knockdown (KD) of Gata2 in mouse bone marrow-derived MCs (BMMCs), which was accelerated by TGF-β stimulation. Since the mRNA levels of Spi1 (encoding transcription factor PU.1) were increased in Gata2 KD BMMCs, we examined the effects of PU.1 on the cell-surface expression of CD103. As expected, CD103 levels on BMMCs were significantly decreased by Spi1 KD and increased by Spi1 overexpression. Spi1 KD suppressed Itgae expression even in the presence of TGF-β in BMMCs and peritoneal MCs, whereas Gata2 KD amplified the TGF-β-induced increase in Itgae expression. The amount of PU.1 binding to the cis-element in the Itgae gene was significantly and moderately increased by Gata2 KD and TGF-β stimulation, respectively. Since PU.1 is an essential transcription factor for dendritic cells (DCs), we examined the role of PU.1 in CD103 cell-surface expression on DCs. The KD experiment using bone marrow-derived DCs (BMDCs) showed a significant decrease in CD103 levels in Spi1-siRNA-transfected BMDCs. We concluded that PU.1 affected CD103 expression on MMCs and DCs by transactivating the Itgae gene, and also that GATA2, which positively regulated the MMC-specific expression of Mcpt1 and Mcpt2, inhibited the cell-surface expression of CD103 by repressing PU.1.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995066","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