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Ligand recognition by 14-3-3 proteins requires negative charges but not necessarily phosphorylation.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2025-01-05 DOI: 10.1002/1873-3468.15077
Seraphine Kamayirese, Laura A Hansen, Sándor Lovas
{"title":"Ligand recognition by 14-3-3 proteins requires negative charges but not necessarily phosphorylation.","authors":"Seraphine Kamayirese, Laura A Hansen, Sándor Lovas","doi":"10.1002/1873-3468.15077","DOIUrl":"https://doi.org/10.1002/1873-3468.15077","url":null,"abstract":"<p><p>Protein-protein interactions involving 14-3-3 proteins regulate various cellular activities in normal and pathological conditions. These interactions have mostly been reported to be phosphorylation-dependent, but the 14-3-3 proteins also interact with unphosphorylated proteins. In this work, we investigated whether phosphorylation is required, or, alternatively, whether negative charges are sufficient for 14-3-3ε binding. We substituted the pThr residue of pT(502-510) peptide by residues with a varying number of negative charges and investigated the binding of the peptides to 14-3-3ε using MD simulations and biophysical methods. We demonstrated that at least one negative charge is required for the peptides to bind 14-3-3ε, although phosphorylation is not necessary, and that two negative charges are preferable for high affinity binding. This discovery opens up new approaches for designing peptide-based 14-3-3 protein inhibitors.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
The [2Fe-2S] cluster of mitochondrial outer membrane protein mitoNEET has an O2-regulated nitric oxide access tunnel.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2025-01-05 DOI: 10.1002/1873-3468.15097
Thao Nghi Hoang, Meritxell Wu-Lu, Alberto Collauto, Peter-Leon Hagedoorn, Madalina Alexandru, Maike Henschel, Shahram Kordasti, Maria Andrea Mroginski, Maxie M Roessler, Kourosh H Ebrahimi
{"title":"The [2Fe-2S] cluster of mitochondrial outer membrane protein mitoNEET has an O<sub>2</sub>-regulated nitric oxide access tunnel.","authors":"Thao Nghi Hoang, Meritxell Wu-Lu, Alberto Collauto, Peter-Leon Hagedoorn, Madalina Alexandru, Maike Henschel, Shahram Kordasti, Maria Andrea Mroginski, Maxie M Roessler, Kourosh H Ebrahimi","doi":"10.1002/1873-3468.15097","DOIUrl":"https://doi.org/10.1002/1873-3468.15097","url":null,"abstract":"<p><p>The mitochondrial outer membrane iron-sulphur ([Fe-S]) protein mitoNEET has been extensively studied as a target of the anti-inflammatory and type-2 diabetes drug pioglitazone and as a protein affecting mitochondrial respiratory rate. Despite these extensive past studies, its molecular function has yet to be discovered. Here, we applied an interdisciplinary approach and discovered an explicit nitric oxide (NO) access site to the mitoNEET [2Fe-2S] cluster. We found that O<sub>2</sub> and pioglitazone block NO access to the cluster, suggesting a molecular function for the mitoNEET [2Fe-2S] cluster in mitochondrial signal transduction. Our discovery hints at a new pathway via which mitochondria can sense hypoxia through O<sub>2</sub> protection of the mitoNEET [2Fe-2S] cluster, a new paradigm in understanding the importance of [Fe-S] clusters for gasotransmitter signal transduction in eukaryotes.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
ABC transporter activity is affected by the size of lipid nanodiscs.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2025-01-02 DOI: 10.1002/1873-3468.15096
Annabella Nouel Barreto, Luis G Cuello, Maria E Zoghbi
{"title":"ABC transporter activity is affected by the size of lipid nanodiscs.","authors":"Annabella Nouel Barreto, Luis G Cuello, Maria E Zoghbi","doi":"10.1002/1873-3468.15096","DOIUrl":"https://doi.org/10.1002/1873-3468.15096","url":null,"abstract":"<p><p>Lipid nanodiscs have become a widely used approach for studying membrane proteins thanks to several advantages they offer. They have been especially useful for studying ABC transporters, despite the growing concern about the possible restriction of the conformational changes of the transporters due to the small size of the discs. Here, we performed a systematic study to determine the effect of the nanodisc size on the ATPase activity of model ABC transporters from human, plant, and bacteria. Our data confirm that the activity of the transporters and their response to regulatory molecules is affected by the nanodisc size. Our findings suggest the use of larger membrane scaffold proteins (MSPs), such as MSP2N2 nanodiscs, to minimize alterations caused by the commonly used small MSP1D1.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
IFNγ and TNFα drive an inflammatory secretion profile in cancer-associated fibroblasts from human non-small cell lung cancer.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2025-01-01 DOI: 10.1002/1873-3468.15083
Lilian Koppensteiner, Layla Mathieson, Liam Neilson, Richard A O'Connor, Ahsan R Akram
{"title":"IFNγ and TNFα drive an inflammatory secretion profile in cancer-associated fibroblasts from human non-small cell lung cancer.","authors":"Lilian Koppensteiner, Layla Mathieson, Liam Neilson, Richard A O'Connor, Ahsan R Akram","doi":"10.1002/1873-3468.15083","DOIUrl":"https://doi.org/10.1002/1873-3468.15083","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are the dominant nonmalignant component of the tumour microenvironment (TME). CAFs demonstrate a high level of inter- and intra-tumour heterogeneity in solid tumours, though the drivers of CAF subpopulations are not fully understood. Here, we demonstrate that non-small cell lung cancer (NSCLC) patient-derived CAFs upregulate the secretion of inflammatory cytokines (IL6, LIF, IL33, GM-CSF, IL1ra) and chemokines (CCL2, CCL3, CCL4, CCL20, CXCL8, CXCL9, CXCL10, CXCL11) in response to in vitro co-culture with anti-CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs) via IFNγ and TNFα. Furthermore, T-cell-derived IFNγ inhibits CXCL12 secretion by CAFs in vitro. Our results highlight the ability of T-cell effector cytokines to modulate the CAF secretome in NSCLC.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Specificity and sensitivity of ALT-associated markers in cancer cells.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2025-01-01 DOI: 10.1002/1873-3468.15087
Ion Udroiu, Jessica Marinaccio, Romina Stella Goffi, Emanuela Micheli, Antonella Sgura
{"title":"Specificity and sensitivity of ALT-associated markers in cancer cells.","authors":"Ion Udroiu, Jessica Marinaccio, Romina Stella Goffi, Emanuela Micheli, Antonella Sgura","doi":"10.1002/1873-3468.15087","DOIUrl":"https://doi.org/10.1002/1873-3468.15087","url":null,"abstract":"<p><p>Some tumors employ a mechanism called alternative lengthening of telomeres (ALT) to counteract telomere shortening-induced replicative senescence. Several hallmarks are used to identify cell lines and tumors as ALT-positive. Here, we analyzed a panel of ALT-positive and -negative cancer cell lines to investigate the specificity and sensibility of ALT-associated markers. We found that all the markers showed high sensitivity, indicating that cells not showing ALT markers are not ALT cells. Conversely, specificity varied significantly, i.e., many markers yield false positives. Detection of false positives may have influenced previous estimations of ALT incidence among tumors. Moreover, claims on the 'coexistence' of ALT and telomerase perhaps should be reconsidered. The findings prompt further study into the nature of these markers and their roles as either part of the ALT machinery or as by-products.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Silica-coated magnetic nanobeads in a flow enrichment target capture Halbach (FETCH) magnetic separation system for circulating tumor cell enrichment.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2025-01-01 DOI: 10.1002/1873-3468.15094
Peng Liu, Sitian He, Anouk Mentink, Pieter Hart, Yongjun Wu, Leon W M M Terstappen, Pascal Jonkheijm, Michiel Stevens
{"title":"Silica-coated magnetic nanobeads in a flow enrichment target capture Halbach (FETCH) magnetic separation system for circulating tumor cell enrichment.","authors":"Peng Liu, Sitian He, Anouk Mentink, Pieter Hart, Yongjun Wu, Leon W M M Terstappen, Pascal Jonkheijm, Michiel Stevens","doi":"10.1002/1873-3468.15094","DOIUrl":"https://doi.org/10.1002/1873-3468.15094","url":null,"abstract":"<p><p>Detecting circulating tumor cells (CTCs) is challenging due to their low presence and heterogeneity. Traditional methods using EpCAM-based separation struggle with CTCs that have undergone epithelial-mesenchymal transition, as this results in lower EpCAM expression. This study presents the use of silica-coated magnetic nanobeads functionalized with streptavidin for CTC capture. Using the FETCH magnetic separation system, we validated the capture efficiency of our beads on tumor cells with varying EpCAM expression. Our beads showed superior capture rates for LNCaP (97%), PC3-9 (91%), PC3 (23%), A549 (22%), and T24 (8%) cells compared to commercial MojoSort™ beads. Despite slightly higher nonspecific binding than CellSearch, our beads demonstrated improved sensitivity for EpCAMlow cells, suggesting they have promise for enhanced CTC capture.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Residues R177 and S178 of the human Na+/H+ antiporter NHA2 are involved in its inhibition by the flavonoid phloretin.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2024-12-31 DOI: 10.1002/1873-3468.15089
Olga Zimmermannova, Martin Kubeš, Tereza Przeczková, Gal Masrati
{"title":"Residues R177 and S178 of the human Na<sup>+</sup>/H<sup>+</sup> antiporter NHA2 are involved in its inhibition by the flavonoid phloretin.","authors":"Olga Zimmermannova, Martin Kubeš, Tereza Przeczková, Gal Masrati","doi":"10.1002/1873-3468.15089","DOIUrl":"https://doi.org/10.1002/1873-3468.15089","url":null,"abstract":"<p><p>The Homo sapiens Na<sup>+</sup>/H<sup>+</sup> antiporter NHA2 (SLC9B2) transports Na<sup>+</sup> or Li<sup>+</sup> in exchange for protons across cell membranes, and its dysfunction results in various pathologies. The activity of HsNHA2 is specifically inhibited by the flavonoid phloretin. Using bioinformatic modeling, we predicted two amino acids (R177 and S178) as being important for the binding of phloretin to the HsNHA2 molecule. Functional expression of HsNHA2 in Saccharomyces cerevisiae and its site-directed mutagenesis revealed that while the R177T mutation resulted in an antiporter that was less sensitive to phloretin, the S178T mutation enhanced the inhibitory effect of phloretin on HsNHA2. Our data corroborate the transport properties of HsNHA2 and its interactions with an inhibitor and can be helpful for the development of new therapeutics targeting this antiporter and its pleiotropic physiological functions.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Cytosolic-enhanced dark Epac-based FRET sensors allow for intracellular cAMP detection in live cells via FLIM.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2024-12-31 DOI: 10.1002/1873-3468.15093
Giulia Zanetti, Jeffrey B Klarenbeek, Kees Jalink
{"title":"Cytosolic-enhanced dark Epac-based FRET sensors allow for intracellular cAMP detection in live cells via FLIM.","authors":"Giulia Zanetti, Jeffrey B Klarenbeek, Kees Jalink","doi":"10.1002/1873-3468.15093","DOIUrl":"https://doi.org/10.1002/1873-3468.15093","url":null,"abstract":"<p><p>Fluorescence resonance energy transfer (FRET)-based biosensors are powerful tools for studying second messengers with high temporal and spatial resolution. FRET is commonly detected by ratio imaging, but fluorescence lifetime imaging microscopy (FLIM), which measures the donor fluorophore's lifetime, offers a robust and more quantitative alternative. We have introduced and optimized four generations of FRET sensors for cAMP, based on the effector molecule Epac1, including variants for either ratio imaging or FLIM detection. Recently, Massengill and colleagues introduced additional mutations that improve cytosolic localization in these sensors, focusing on constructs optimized for ratio imaging. Here we present and briefly characterize these mutations in our dedicated FLIM sensors, finding they enhance cytosolic localization while maintaining performance comparable to original constructs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Cell cycle-dependent regulation of CRISPR-Cas9 repetitive activation by anti-CRISPR and Cdt1 fusion in the CRISPRa system.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2024-12-30 DOI: 10.1002/1873-3468.15090
Kanae Kishi, Kiyomi Nigorikawa, Yuki Hasegawa, Yusaku Ohta, Erina Matsugi, Daisuke Matsumoto, Wataru Nomura
{"title":"Cell cycle-dependent regulation of CRISPR-Cas9 repetitive activation by anti-CRISPR and Cdt1 fusion in the CRISPRa system.","authors":"Kanae Kishi, Kiyomi Nigorikawa, Yuki Hasegawa, Yusaku Ohta, Erina Matsugi, Daisuke Matsumoto, Wataru Nomura","doi":"10.1002/1873-3468.15090","DOIUrl":"https://doi.org/10.1002/1873-3468.15090","url":null,"abstract":"<p><p>CRISPR-Cas9 is a widely used genome-editing tool. We previously developed a method with improved homology-directed repair efficiency and reduced off-target effects by utilizing a fusion protein of AcrIIA4, a Cas9 inhibitor, and Cdt1, which accumulates in the G1 phase and activates Cas9 only in the S/G2 phase. However, it is unknown whether Cas9 inhibition by AcrIIA4 + Cdt1 occurs repeatedly in the G1 phase as the cell cycle progresses. In this study, we used the CRISPRa system to monitor changes in the interaction between Cas9 and AcrIIA4 + Cdt1 at single-cell resolution and in real time. Our findings are among the few examples of successful detection of fluctuating protein-protein interactions that oscillate over time.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Insights into the renal pathophysiology in Hermansky-Pudlak syndrome-1 from urinary extracellular vesicle proteomics and a new mouse model.
IF 3.5 4区 生物学
FEBS Letters Pub Date : 2024-12-30 DOI: 10.1002/1873-3468.15088
Dawn M Maynard, Bernadette R Gochuico, Hadass Pri Chen, Christopher K E Bleck, Patricia M Zerfas, Wendy J Introne, William A Gahl, May C V Malicdan
{"title":"Insights into the renal pathophysiology in Hermansky-Pudlak syndrome-1 from urinary extracellular vesicle proteomics and a new mouse model.","authors":"Dawn M Maynard, Bernadette R Gochuico, Hadass Pri Chen, Christopher K E Bleck, Patricia M Zerfas, Wendy J Introne, William A Gahl, May C V Malicdan","doi":"10.1002/1873-3468.15088","DOIUrl":"https://doi.org/10.1002/1873-3468.15088","url":null,"abstract":"<p><p>Hermansky-Pudlak syndrome type 1 (HPS-1) is a rare, autosomal recessive disorder caused by defects in the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Impaired kidney function is among its clinical manifestations. To investigate HPS-1 renal involvement, we employed 1D-gel-LC-MS/MS and compared the protein composition of urinary extracellular vesicles (uEVs) from HPS-1 patients to normal control individuals. We identified 1029 proteins, 149 of which were altered in HPS-1 uEVs. Ingenuity Pathway Analysis revealed disruptions in mitochondrial function and the LXR/RXR pathway that regulates lipid metabolism, which is supported by our novel Hps1 knockout mouse. Serum concentration of the LXR/RXR pathway protein ApoA1 in our patient cohort was positively correlated with kidney function (with the estimated glomerular filtration rate or eGFR). uEVs can be used to study epithelial cell protein trafficking in HPS-1 and may provide outcome measures for HPS-1 therapeutic interventions.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
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