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Boosting the thermal stability and catalytic efficiency of Sulfurihydrogenibium yellowstonense carbonic anhydrase through proline substitutions. 通过脯氨酸取代提高硫氢黄酮碳酸酐酶的热稳定性和催化效率。
IF 4.2
The FEBS journal Pub Date : 2025-08-10 DOI: 10.1111/febs.70211
Shima Ghaedizadeh, Majid Zeinali, Khosro Khajeh, Ali Mohammad Banaei-Moghaddam
{"title":"Boosting the thermal stability and catalytic efficiency of Sulfurihydrogenibium yellowstonense carbonic anhydrase through proline substitutions.","authors":"Shima Ghaedizadeh, Majid Zeinali, Khosro Khajeh, Ali Mohammad Banaei-Moghaddam","doi":"10.1111/febs.70211","DOIUrl":"https://doi.org/10.1111/febs.70211","url":null,"abstract":"<p><p>The urgent need to address global warming necessitates the development of advanced technologies for carbon capture and storage (CCS). Although carbon dioxide absorption into alkanolamines or carbonate solutions is among the most common CCS processes, these approaches harbor some limitations. Carbonic anhydrase enzymes can significantly increase the efficacy of CO<sub>2</sub> absorption into capture solvent solutions. Carbonic anhydrase from Sulfurihydrogenibium yellowstonense (SspCA) is a well-known enzyme with favorable properties for CO<sub>2</sub> absorption into capture solutions. Here, using computational tools, strategic proline substitutions were designed to enhance the thermal stability of SspCA. Compared to the wild type, the engineered mutants, E145P and N153P, showed an increase of 1.6-4.3 °C in the melting temperature. After 14 h at 80 °C, the wild type retained only 6% ± 1% of its initial activity, while N153P and E145P retained 33% ± 3% and 44% ± 1%, respectively. The E145P and N153P mutants in aqueous potassium carbonate medium at 60 °C outperformed the wild type in retention of CO<sub>2</sub> hydration activity. In addition, an increase in the catalytic efficiency of the E145P mutant, along with a decrease in its K<sub>m</sub> value, indicated that proline substitution facilitates substrate binding. Molecular dynamics simulations exhibited the proline-induced structural changes, particularly reduced terminal fluctuations. Structural studies unveiled the formation of a new salt bridge connecting the C- and N-terminal regions of carbonic anhydrase, contributing to reduced fluctuations and enhanced stability. This study underscores the success of introducing proline substitutions in fortifying carbonic anhydrase stability and catalytic efficacy, which is vital for enzymatic carbon capture and storage technologies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812820","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
Gasdermins: multifunctional effectors of membrane permeabilization across cellular compartments. Gasdermins:跨细胞区室膜渗透的多功能效应器。
IF 4.2
The FEBS journal Pub Date : 2025-08-10 DOI: 10.1111/febs.70215
Eleonora Margheritis, Nadine Gehle, Katia Cosentino
{"title":"Gasdermins: multifunctional effectors of membrane permeabilization across cellular compartments.","authors":"Eleonora Margheritis, Nadine Gehle, Katia Cosentino","doi":"10.1111/febs.70215","DOIUrl":"https://doi.org/10.1111/febs.70215","url":null,"abstract":"<p><p>Members of the gasdermin (GSDM) family are pore-forming proteins primarily known for executing inflammatory cell death known as pyroptosis. GSDM-mediated pore formation at the plasma membrane (PM) facilitates the selective secretion of immunomodulatory proteins and nonselective ionic fluxes during pyroptotic signaling. Recent findings suggest that GSDMs also modulate intracellular processes by associating with and altering membranes in various organelles, including mitochondria, lysosomes, endoplasmic reticulum (ER), and the nucleus. These activities may trigger alternative signaling pathways that do not necessarily involve PM perforation. In this review, we explore the diverse mechanisms of GSDM association across organelle membranes and discuss the physiological and pathological implications of GSDM-induced membrane integrity alteration.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812822","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
CRISPR-Cas9 screen reveals that inhibition of enhancer of zeste homolog 2 sensitizes malignant T cells to dimethyl-fumarate-induced cell death. CRISPR-Cas9筛选显示,抑制zeste同源物2增强子可使恶性T细胞对富马酸二甲酯诱导的细胞死亡增敏。
IF 4.2
The FEBS journal Pub Date : 2025-08-01 DOI: 10.1111/febs.70208
Jan P Teubner, Deniz Tümen, Arne Kandulski, Philipp Heumann, Patricia Mester, Elisabeth Aschenbrenner, Kirstin Pollinger, Manuela Gunckel, Barbara Volz, Tobias Hein, Paul L Beltzig, Luisa Tengler, Florian Voll, Marina Kreutz, Claudia Kunst, Jan P Nicolay, Martina Müller, Karsten Gülow
{"title":"CRISPR-Cas9 screen reveals that inhibition of enhancer of zeste homolog 2 sensitizes malignant T cells to dimethyl-fumarate-induced cell death.","authors":"Jan P Teubner, Deniz Tümen, Arne Kandulski, Philipp Heumann, Patricia Mester, Elisabeth Aschenbrenner, Kirstin Pollinger, Manuela Gunckel, Barbara Volz, Tobias Hein, Paul L Beltzig, Luisa Tengler, Florian Voll, Marina Kreutz, Claudia Kunst, Jan P Nicolay, Martina Müller, Karsten Gülow","doi":"10.1111/febs.70208","DOIUrl":"https://doi.org/10.1111/febs.70208","url":null,"abstract":"<p><p>Constitutive activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a hallmark of many lymphocyte-associated cancers, including cutaneous T-cell lymphoma (CTCL) and its leukemic variant, the Sézary syndrome. Dimethyl fumarate (DMF) has been identified as a promising NF-κB-targeted therapy and has shown positive outcomes in a phase II clinical trial involving patients with Sézary syndrome. However, limited responsiveness remains a significant challenge. Through a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen, we identified enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase) as a critical target for enhancing DMF-induced cell death. EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is responsible for the methylation of histone H3 (H3K27). Combining DMF with the US Food and Drug Administration (FDA)-approved EZH2 inhibitor tazemetostat significantly increases cell death in patient-derived CTCL cells, offering a promising strategy to improve therapeutic outcomes and overcome limited responsiveness to DMF.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765957","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
Principal mechanisms of extracellular matrix-mediated cell-cell communication in physiological and tumor microenvironments. 生理和肿瘤微环境中细胞外基质介导的细胞间通讯的主要机制。
IF 4.2
The FEBS journal Pub Date : 2025-08-01 DOI: 10.1111/febs.70207
Zoi Piperigkou, Sylvia Mangani, Nikolaos E Koletsis, Christos Koutsakis, Nicholas S Mastronikolis, Marco Franchi, Nikos K Karamanos
{"title":"Principal mechanisms of extracellular matrix-mediated cell-cell communication in physiological and tumor microenvironments.","authors":"Zoi Piperigkou, Sylvia Mangani, Nikolaos E Koletsis, Christos Koutsakis, Nicholas S Mastronikolis, Marco Franchi, Nikos K Karamanos","doi":"10.1111/febs.70207","DOIUrl":"https://doi.org/10.1111/febs.70207","url":null,"abstract":"<p><p>Cell-cell communication is essential for the regulated exchange of information between cells, coordinating critical cellular processes under physiological and pathological conditions. The extracellular matrix (ECM) is a complex three-dimensional (3D) intercellular macromolecular network that provides structural support to tissues, while actively modulating cellular functions and responses. ECM-mediated intercellular communication is a key player in both homeostasis and disease development. Particularly in cancer, ECM reorganization drives tumor development and progression, shaping dynamic interactions within the tumor microenvironment (TME). In this review, we present and discuss two principal mechanisms of matrix-mediated cell-cell communication in both physiological and cancerous contexts. First, we explore the impact of ECM biomechanical properties in mechanical sensing and communication, which govern key aspects of cell signaling, adhesion, and migration across normal and malignant tissues. Second, we discuss the role of the ECM in facilitating cell-cell communication through the controlled release and navigation of extracellular vesicles (EVs). EVs carry, among other constituents, proteins, enzymes, microRNAs (miRNAs), and signaling molecules that relay information to nearby or distant cells, modulating the initiation of metastasis and pre-metastatic niche formation. Conclusively, in this review, we highlight the critical role of targeting ECM dynamics in cell-cell communication under physiological processes and during cancer progression. Targeted therapies that modulate ECM components and interactions with cells hold promise for future treatment approaches.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762902","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
Biophysical characterization and interaction study of WhiB6 protein of Mycobacterium tuberculosis with espA. 结核分枝杆菌WhiB6蛋白与espA的生物物理特性及相互作用研究。
IF 4.2
The FEBS journal Pub Date : 2025-07-29 DOI: 10.1111/febs.70202
Teena, Sonam Kumari, Ruchi Singh, Soumik Siddhanta, Shashank Deep
{"title":"Biophysical characterization and interaction study of WhiB6 protein of Mycobacterium tuberculosis with espA.","authors":"Teena, Sonam Kumari, Ruchi Singh, Soumik Siddhanta, Shashank Deep","doi":"10.1111/febs.70202","DOIUrl":"https://doi.org/10.1111/febs.70202","url":null,"abstract":"<p><p>Tuberculosis is an intractable disease because of the peculiar nature of the virulent properties of Mycobacterium tuberculosis (Mtb). The probable transcriptional regulator WhiB6 protein plays a crucial role in the virulence systems of Mtb. It regulates the expression of genes essential for the virulence pathways by binding to their promoter region; espA (encoding ESX-1 secretion-associated protein EspA) is one such gene. Herein, we have used biophysical methods, including steady-state intrinsic fluorescence spectroscopy, circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC), and surface-enhanced Raman spectroscopy (SERS), to understand the interaction of apo-WhiB6 protein with espA promoter DNA. For the first time, we report the conformational details and biophysical parameters related to the WhiB6-espA-promoter-DNA interaction. WhiB6 binds to the DNA with moderate affinity, as revealed by ITC. It is an entropy-driven process, signifying the importance of hydrophobic interaction and an increase in conformational flexibility upon binding. Addition of salt changes the binding from endothermic to exothermic, revealing the increase in electrostatic interaction between protein and DNA with concomitant decrease in flexibility. CD and SERS studies suggest subtle perturbation in the secondary conformation of the protein upon binding to the DNA. ITC titration data of an arginine-to-leucine mutant in the arginine-rich region (GRARAF) of WhiB6 suggest involvement of these residues in the binding with DNA. Preventing the binding of WhiB6 with promoter DNA of the virulence genes can hinder the functioning of Mtb and hence can act as an effective therapeutic intervention for tuberculosis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746611","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
Unconventional structure and function of PHD domains from additional sex combs-like proteins. 来自额外性梳状蛋白的PHD结构域的非常规结构和功能。
IF 4.2
The FEBS journal Pub Date : 2025-07-29 DOI: 10.1111/febs.70206
Cameron J Reddington, Annabel R Walsh, Torsten Kleffmann, Christoph Göbl, Peter D Mace
{"title":"Unconventional structure and function of PHD domains from additional sex combs-like proteins.","authors":"Cameron J Reddington, Annabel R Walsh, Torsten Kleffmann, Christoph Göbl, Peter D Mace","doi":"10.1111/febs.70206","DOIUrl":"https://doi.org/10.1111/febs.70206","url":null,"abstract":"<p><p>The polycomb repressive-deubiquitinase (PR-DUB) complex removes ubiquitin from lysine residue 119 on histone H2A (H2AK119Ub) in humans. The PR-DUB is composed of two central protein factors, the catalytic breast cancer type 1 susceptibility protein (BRCA1)-activating protein 1 (BAP1) and one of three additional sex combs-like 1-3 (ASXL1-3) proteins. A plant homeodomain (PHD) at the C terminus of ASXL proteins is recurrently truncated in cancer, was previously proposed to recognise epigenetic modifications on the N-terminal tail of histone H3 and was recently shown to bind an auxiliary set of PR-DUB interactors, named methyl CpG-binding domain proteins 5 (MBD5) and 6 (MBD6). Here, we demonstrate that the ASXL PHD domain lacks features required for histone tail recognition and is unable to bind histone H3 epigenetic marks. Modelling the structure of the ASXL PHD using AlphaFold3 suggests that the domain has an atypical fold and that the isolated ASXL PHD can chelate a single zinc ion in vitro, compared with the two ions conventionally bound by PHD domains. Alternatively, we show that the ASXL PHD-MBD5 and PHD-MBD6 complexes are stable in vitro. A composite zinc-binding site was shown to form at the interface between the ASXL2 PHD and MBD6 MBD domains, and is required for stable complex formation. Overall, these data suggest an unconventional pairing of domains coordinate key functions of the PR-DUB-a noncanonical PHD domain from ASXL proteins partners with MBD5 or 6, which were themselves misannotated because they cannot bind to methylated DNA.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746613","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
Crystal structure-guided revelation of metal ion-dependent functional ambiguity in Pseudomonas aeruginosa histidinol dehydrogenase. 晶体结构引导下铜绿假单胞菌组氨酸脱氢酶中金属离子依赖功能歧义的揭示。
IF 4.2
The FEBS journal Pub Date : 2025-07-29 DOI: 10.1111/febs.70209
Gourab Basu Choudhury, Rakesh Chatterjee, Angira Saha, Dhruba Jyoti Sarkar, Basanta Kumar Das, Saumen Datta
{"title":"Crystal structure-guided revelation of metal ion-dependent functional ambiguity in Pseudomonas aeruginosa histidinol dehydrogenase.","authors":"Gourab Basu Choudhury, Rakesh Chatterjee, Angira Saha, Dhruba Jyoti Sarkar, Basanta Kumar Das, Saumen Datta","doi":"10.1111/febs.70209","DOIUrl":"https://doi.org/10.1111/febs.70209","url":null,"abstract":"<p><p>Histidinol dehydrogenase (HisD) is an enzyme that catalyzes the final step in histidine biosynthesis, converting l-histidinol to l-histidine, and plays a crucial role in bacterial metabolism. In this study, we investigated the ambiguity in catalytic mechanisms of the HisD enzyme in Pseudomonas aeruginosa using biochemical and structural approaches, particularly through X-ray crystallography. The primary objective of this research was to explore the structural and functional variability of PaHisD and provide knowledge for potential therapeutic developments in this organism. Our findings reveal significant structural alterations in the enzyme as we identified a new substrate-binding pocket due to structural rearrangements. We also confirmed the presence of an additional metal ion (Zn<sup>2+</sup>), contributing to its catalytic ambiguity. Given its relevance in molecular drug targeting, we examined how the differences in NAD<sup>+</sup> and substrate binding could impact the efficacy of existing inhibitors. Computational studies further evaluated the variability in inhibitor binding, providing new insights for designing more effective therapeutic agents targeting PaHisD.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746612","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
Chromatin folding by the Polycomb group proteins and its elusive role in epigenetic repression. Polycomb蛋白的染色质折叠及其在表观遗传抑制中的作用。
IF 4.2
The FEBS journal Pub Date : 2025-07-27 DOI: 10.1111/febs.70199
Ludvig Lizana, Yuri B Schwartz
{"title":"Chromatin folding by the Polycomb group proteins and its elusive role in epigenetic repression.","authors":"Ludvig Lizana, Yuri B Schwartz","doi":"10.1111/febs.70199","DOIUrl":"https://doi.org/10.1111/febs.70199","url":null,"abstract":"<p><p>The Polycomb system epigenetically represses selected developmental genes to enforce gene expression programs of differentiated cells. The system requires the coordinated action of dozens of structurally unrelated proteins assembled in two evolutionarily conserved polycomb repressive complexes, PRC1 and PRC2. Genes repressed by the Polycomb system are enriched in histone H3 trimethylated at lysine 27 (H3K27me3), an epigenetic mark that propagates the repressed state after DNA replication. Despite the impressive progress in dissecting molecular functions of the Polycomb group proteins, the fundamental questions of how the Polycomb system represses transcription or how the H3K27me3 mark is translated to benefit the repression are still open. Multiple observations indicate that the binding of PRC1, PRC2, and elevated H3K27me3 correlate with changes in the chromatin structure of target genes, which may be integral for the associated epigenetic repression. In this Review, we summarize our current understanding of these observations. We discuss the chromatin folding inside the loci repressed by the Polycomb system, consider molecular processes causing it and reflect upon its possible impact on transcription and epigenetic memory of the repressed state.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736458","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
Platelets in the regulation of glucose and lipid metabolism—functions beyond the maintenance of vascular integrity are being revealed 血小板在调节葡萄糖和脂质代谢中的作用——其功能超出了维持血管的完整性。
IF 4.2
The FEBS journal Pub Date : 2025-07-27 DOI: 10.1111/febs.70198
Katarzyna Kolczyńska-Matysiak, Toufic Kassouf, David Stegner, Grzegorz Sumara
{"title":"Platelets in the regulation of glucose and lipid metabolism—functions beyond the maintenance of vascular integrity are being revealed","authors":"Katarzyna Kolczyńska-Matysiak,&nbsp;Toufic Kassouf,&nbsp;David Stegner,&nbsp;Grzegorz Sumara","doi":"10.1111/febs.70198","DOIUrl":"10.1111/febs.70198","url":null,"abstract":"<p>Platelets, small anucleate blood cells, are essential not only for maintaining vascular integrity but also for broader systemic homeostasis. Traditionally recognized for their role in preventing hemorrhage following injury, recent research has revealed their involvement in a range of metabolic processes. Notably, platelets contribute to the regulation of insulin secretion, glucose blood levels, adipose tissue metabolism, and liver function. Furthermore, they have been implicated in the development of metabolic disorders, such as type 2 diabetes, obesity, and liver diseases. This review highlights the latest insights into how platelets influence key organs involved in systemic metabolic regulation.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"292 19","pages":"4992-5007"},"PeriodicalIF":4.2,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Posttranslational modifications of phosphodiesterase type 4 enzymes represent novel points for therapeutic targeting. 磷酸二酯酶4型酶的翻译后修饰代表了新的治疗靶点。
IF 4.2
The FEBS journal Pub Date : 2025-07-27 DOI: 10.1111/febs.70205
Madihah Hussain, Gonzalo S Tejeda, George S Baillie
{"title":"Posttranslational modifications of phosphodiesterase type 4 enzymes represent novel points for therapeutic targeting.","authors":"Madihah Hussain, Gonzalo S Tejeda, George S Baillie","doi":"10.1111/febs.70205","DOIUrl":"https://doi.org/10.1111/febs.70205","url":null,"abstract":"<p><p>Cyclic AMP is a second messenger that is produced in response to the activation of many G-protein-coupled receptors. As each receptor type is linked to a transient but distinct physiological outcome, the activation of cAMP effector proteins is highly compartmentalized by the action of phosphodiesterases (PDEs). Phosphodiesterase type 4 (PDE4) enzymes are expressed as 25 different isoforms, and the function of each protein is linked to its cellular location(s). Fine-tuning of cAMP dynamics in space and time is underpinned by PDE4 activity shifts or PDE4 translocations that are driven by posttranslational modifications. As 'omics' technology improves, we are now learning more about these PDE4 events, and we can link them to diseases where aberrant cAMP signaling is causative. Additionally, recent advances allow us to pinpoint specific PDE4 modifications with targeted therapies that will lessen the chances of side effects. This review charts all known PDE4 modifications and links them to innovative existing pharmaceutical concepts or possible future therapeutic developments.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736460","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
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