FEBS Open Bio最新文献

{"title":"Molecular dynamics simulations of positively selected codons in FcγRI reveal novel biochemical binding properties","authors":"David A. Young,&nbsp;Omar Arias-Gaguancela,&nbsp;Fiona Gibson,&nbsp;Morgan Grainger,&nbsp;Jodie Score,&nbsp;Amit Nathubhai,&nbsp;Mauricio Cafiero,&nbsp;Lee Richard Machado","doi":"10.1002/2211-5463.70247","DOIUrl":"10.1002/2211-5463.70247","url":null,"abstract":"<p>FcγRI is a high-affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene, <i>FCGR1A,</i> using codon-based selection tests on aligned 1–1 orthologous sequences from placental mammals (<i>n</i> = 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H¹⁴⁸ (M2a ω 0.997 &amp; M8 ω = 0.993)) and (W¹⁴⁹ (M2a ω = 0.999 &amp; M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H¹⁴⁸P and W¹⁴⁹R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI-IgG of modern-day <i>Homo sapiens</i>. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H¹⁴⁸P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W¹⁴⁹R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI-IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":"16 9","pages":"1708-1725"},"PeriodicalIF":2.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A yeast model of 5-oxoproline accumulation reveals a general toleration to 5-oxoproline","authors":"Pratiksha Dubey,&nbsp;Vaishnavi Sanjayan,&nbsp;Praveen Singh,&nbsp;Shantanu Sengupta,&nbsp;Anand Kumar Bachhawat","doi":"10.1002/2211-5463.70254","DOIUrl":"10.1002/2211-5463.70254","url":null,"abstract":"<p>5-oxoproline (5-OP) or pyroglutamic acid is an intermediate in the degradation arc of the glutathione cycle. It is metabolized into glutamate through the action of the 5-oxoprolinase enzyme, the only enzyme known to act on this metabolite. 5-OP has long been known to be relatively inert with a proposed role as an osomoprotectant. Recent studies on the 5-oxoprolinase enzyme in mammalian cells have, however, shown that knockdown or deletion of 5-oxoprolinase makes mice (and humans) prone to heart failure, an effect ascribed to oxidative stress caused by a twofold increase in 5-OP. To examine the consequences of 5-oxoproline accumulation more rigorously, we created a yeast model for 5-oxoproline accumulation. Using this model, we observed retardation of growth only when intracellular levels of 5-OP were increased 12- to 20-fold over normal levels. Performing an analysis of transcriptomic changes under these conditions, we observed a large number of genes were differentially regulated and while there was no unifying dysregulated pathway, there was an upregulation of various efflux pumps. Ultimately, modulating the expression of these genes by knockout or overexpression highlighted that many of the upregulated genes were involved in the cellular response to 5-OP accumulation. However, our results failed to show any significant oxidative stress response. In conclusion, our study suggests a need to reevaluate previous suppositions of the 5-OP induced oxidative stress response and proposes alternate mechanisms for this effect.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":"16 9","pages":"1752-1765"},"PeriodicalIF":2.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.","authors":"Lishen Wang, Mingqiang Deng, Dongmei He, Diqin Lai, Dongjun Liu, Dengyong Zhu, Zhenhua Zhang, Peng Tang, Chuanman Zhou, Menghui Yin, Xichen Bao","doi":"10.1002/2211-5463.70297","DOIUrl":"10.1002/2211-5463.70297","url":null,"abstract":"<p><p>The Warburg effect has long suggested that oxidative phosphorylation (OXPHOS) is dispensable for tumor growth. However, recent studies have shown that the mitochondrial RNA polymerase inhibitors IMT1 and IMT1b, which impair OXPHOS, are potent anticancer agents. Here, we demonstrate that ionomycin, a selective ionophore known to modulate mitochondrial homeostasis, similarly inhibits mitochondrial gene expression across cancer cell lines. Specifically, gene expression and nascent RNA profiling revealed a global downregulation of mitochondrial gene transcription in Jurkat T, THP-1, HeLa, and NCI-H441 cells. Thus, we conclude that ionomycin suppressed mitochondrial gene transcription, impaired OXPHOS, and thereby inhibited cancer cell proliferation and growth, providing a novel insight into the function of ionomycin.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic dissection of human ABCE1 in yeast reveals separable requirements for ribosome recycling and suppression of aberrant reinitiation.","authors":"Eriko Nakata, Yuxin Li, Kei Endo, Koichi Ito","doi":"10.1002/2211-5463.70337","DOIUrl":"10.1002/2211-5463.70337","url":null,"abstract":"<p><p>The ATP-binding cassette E1 (ABCE1) protein is an essential factor for ribosome recycling, splitting post-termination ribosomes into subunits for subsequent rounds of translation. Despite high conservation, human ABCE1 (hABCE1) fails to functionally complement the depletion of its essential yeast homolog, Rli1. In this study, we leveraged this species-specificity to dissect the functional architecture of ABCE1. Through analysis of yeast-human chimeric proteins, we identified the N-terminal nucleotide-binding domain (NBD1) as the primary determinant of this incompatibility. To further investigate, we isolated multiple hABCE1 point mutants (revertants) that successfully restored yeast growth. We then developed a novel dual-luciferase reporter assay to quantify aberrant translation reinitiation in the 3'UTR, an event recognized as a direct consequence of ABCE1 deficiency. Notably, while the revertant mutants rescued yeast viability, they failed to suppress aberrant reinitiation, exhibiting levels equivalent to the nonfunctional hABCE1. This genetic uncoupling of viability from the suppression of reinitiation suggests that the canonical ribosome recycling function required for cell growth and the role in preventing aberrant reinitiation have distinct functional thresholds or are genetically separable aspects of ABCE1 activity.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell surface CD11c as a neutrophil aging marker molecule.","authors":"Sophia Koutsogiannaki, Fahd Alhamdan, Erik Malm, Marie Bermudez, Samuel Y Kim, Koichi Yuki","doi":"10.1002/2211-5463.70332","DOIUrl":"10.1002/2211-5463.70332","url":null,"abstract":"<p><p>Neutrophils exhibit substantial functional heterogeneity shaped by both developmental stage and cellular maturation, but their mechanisms remain incompletely defined. CD11c (ITGAX) is traditionally considered as a cell surface marker of dendritic cells. We recently reported that it is highly expressed intracellularly in neutrophils and contributes to their maturation; however, its role at the cell surface is unclear. Here, we showed that surface CD11c expression level was heterogeneous across neutrophils, enabling classification into CD11c^hi and CD11c^-/lo populations. CD11c^hi neutrophils display enhanced phagocytic capacity and features of neutrophil aging, including increased CXCR4 and reduced CD62L expression. Bulk RNA sequencing across the three pediatric age groups revealed that differentially expressed genes (DEGs) between CD11c^hi and CD11c^-/lo neutrophils were observed most in infants followed by preschool age children. Infant neutrophils exhibited reduced phagocytic capacity and distinct gene expression patterns compared to older children. Functional interrogation of candidate genes (ANXA2, COL6A3, DCN) demonstrated their role in regulating phagocytosis without affecting reactive oxygen species production. Machine learning analysis further identified age-dependent ontology of the DEGs associated with cell surface CD11c expression, including pathways related to adhesion, extracellular matrix interactions, stress responses, and metabolic regulation. Integrative network analysis positioned CD11c linked to cytoskeletal remodeling and phagocytosis. Collectively, these findings support a model in which developmental age establishes the baseline transcriptional landscape of neutrophils, while CD11c serves as a marker of neutrophil aging rather than acting as a primary driver of transcriptional reprogramming.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative assessment of crystallographic and cryo-EM models in the Protein Data Bank.","authors":"Alexander Wlodawer, Pawel Rubach, Zbigniew Dauter, Wojciech Dec, Dariusz Brzezinski, Marta Kulik, Wladek Minor, Mariusz Jaskolski","doi":"10.1002/2211-5463.70326","DOIUrl":"10.1002/2211-5463.70326","url":null,"abstract":"<p><p>With cryogenic electron microscopy (cryo-EM) on track to surpass X-ray crystallography as the preferred method for determining macromolecular structures, it is important to evaluate and compare the quality of structure models obtained by these methods. This allows us to assess whether the rapidly growing numbers (quantity) correlate with quality and to identify areas in which each method excels or falls short. Selected quality-related parameters were compared for 97 200 crystal structures and 30 139 cryo-EM structures released by the Protein Data Bank (PDB) between 2015 and 2025. Comparison of geometric and stereochemical parameters indicated that, despite significant differences in the resolution of the experimental data, these values were, in the vast majority of cases, close to the expected targets. Nevertheless, we found that crystal structures tend to exhibit more Ramachandran and rotamer outliers than cryo-EM structures, although they unexpectedly have lower clashscore values. Separately, we compared the quality of 612 crystal and 1817 cryo-EM structures in the PDB representing complete ribosomes or their subunits. For this subset of very large, well-defined macromolecules, we found that the quality of many cryo-EM models is higher than that of their crystal counterparts, and that the best cryo-EM structures were also determined at higher resolution. Overall, we conclude that the availability of both techniques has clearly resulted in major advances during the last decade and bodes very well for the future.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salmonella enterica serovar typhi limits the potency of typhoid toxin and ADP-ribosylating toxin AB to establish a persistent infection.","authors":"Maria C Zabala-Rodriguez, Juliette K Tinker, Teresa Frisan, Taj Azarian, Ken Teter","doi":"10.1002/2211-5463.70329","DOIUrl":"10.1002/2211-5463.70329","url":null,"abstract":"<p><p>Chronic infection is important for the transmission of Salmonella enterica serovar Typhi (S. Typhi), an obligate human pathogen responsible for typhoid fever. The immunomodulatory action of typhoid toxin helps establish an initial stealth invasion of the intestinal tract that can lead to systemic spread, colonization of the gallbladder, and persistent shedding. Typhoid toxin contains a cell-binding pentamer and two catalytic subunits: cytolethal distending toxin B (CdtB, a DNase) and pertussis-like toxin A (PltA, an ADP-ribosyltransferase). It undergoes endocytosis and transport to the endoplasmic reticulum (ER) where toxin disassembly occurs. This allows the catalytic subunits to exit the ER for interaction with their nuclear or cytosolic targets. However, all known cellular and physiological effects of typhoid toxin are attributed to CdtB. These effects reduce the severity of intestinal inflammation, promoting host survival and long-term infections. PltA has in vitro enzymatic activity but does not affect cells challenged with typhoid toxin. It is thought that the cytosolic action of PltA will be identified in future work. We instead propose that PltA never reaches the cytosol: it is retained in the ER to limit toxin potency, thereby allowing the anti-inflammatory effects of CdtB to promote intestinal colonization. The absence of Salmonella ADP-ribosylating toxin AB (ArtAB) from all strains of S. Typhi may serve a similar purpose. We accordingly propose a model of balanced pathogenicity in which the lack of toxin ADP-ribosyltransferase activity is essential for S. Typhi pathogenesis.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148826601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCG vaccination potentiates oxidative phosphorylation in neonatal myeloid-derived suppressor cells.","authors":"Yingying Chen, Hui Li","doi":"10.1002/2211-5463.70333","DOIUrl":"10.1002/2211-5463.70333","url":null,"abstract":"<p><p>Bacillus Calmette-Guérin (BCG) vaccination has well-documented off-target effects in early life, but the underlying molecular mechanisms remain incompletely understood. This study investigated whether BCG reprograms neonatal myeloid-derived suppressor cells (MDSCs) through oxidative phosphorylation (OXPHOS). After neonatal mice received a subcutaneous injection of BCG or PBS, the effects of BCG exposure on splenic monocytic (M-) and polymorphonuclear (PMN-) MDSCs were assessed. BCG vaccination significantly increased the expression of OXPHOS-related genes (Ndufab1, Sdhd, Uqcrfs1, Cox4i) and mitochondrial oxidative activity in both MDSC subsets. Seahorse analysis revealed a higher oxygen consumption rate in BCG-exposed PMN-MDSCs. Functional assays showed that BCG impaired MDSC-mediated T-cell suppression, with oligomycin treatment partially able to restore this suppressive capacity. Together, these findings indicate that BCG-induced OXPHOS potentiation contributes to the loss of MDSC immunosuppressive function in neonatal mice, providing a molecular mechanism for the non-specific immunomodulatory effects of BCG vaccination early in life.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and biochemical insights into the thermostable esterase Ta0887 from Thermoplasma acidophilum.","authors":"Alejandro Delgado-Rey, Miriam Livier Llamas-García, Gabriela M Montero-Morán, Leticia Santos, Samuel Lara-González","doi":"10.1002/2211-5463.70327","DOIUrl":"10.1002/2211-5463.70327","url":null,"abstract":"<p><p>Microbial esterases are versatile and stable enzymes with a wide range of biotechnological applications. However, few esterases have been characterized from archaea, an important source of extremophilic enzymes. In this study, we report the biochemical characterization and crystal structure of Ta0887, a novel esterase from the thermoacidophilic archaeon Thermoplasma acidophilum. The protein was successfully cloned, expressed, and purified in Escherichia coli. Light scattering assays revealed that Ta0887 is a monomer in solution. Activity assays using p-nitrophenyl (p-NP) esters confirmed its esterase activity, showing a substrate preference for p-NP hexanoate (C6). Furthermore, the substitution of Ser95 with alanine completely abolished enzymatic activity, thereby confirming its essential role as the nucleophilic residue of the catalytic triad. The enzyme exhibited optimal activity at 65 °C and pH 8.0. Notably, Ta0887 displayed high thermal stability, retaining 66% residual activity after incubation at 80 °C for 2 h, consistent with its thermal denaturation midpoint temperature of 80.6 °C. The crystal structure of Ta0887, resolved at 1.93 Å, revealed an α/β-hydrolase core domain consisting of an eight-strand β-sheet, surrounded by seven α-helices, and a cap domain comprising four α-helices. Ta0887 features a large substrate-binding pocket at the interface between the two domains that contains the conserved residues Ser95, Asp187, and His215 of the catalytic triad. Further analysis indicates that an efficiently packed hydrophobic core is a key feature for the observed thermostability. The findings from this study provide a basis for the future engineering of Ta0887 with the aim of enhancing its potential for industrial and biotechnological applications.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13498779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From patient advocacy to patient-driven research: Building active partnerships beginning at the bench to reach the bedside.","authors":"Jenica H Kakadia, Rachel Heilmann, Maximiliano Barrientos, Laura MacNeill, Ingrid Vallee, Sarah K Schultz, Patrick O'Donoghue, Angelica A Moresco, Victoria M Siu, Ilka U Heinemann","doi":"10.1002/2211-5463.70318","DOIUrl":"https://doi.org/10.1002/2211-5463.70318","url":null,"abstract":"<p><p>Patient advocates offer lived experience that can shape research priorities, methods, and outcomes. Patient engagement contributes valuable resources to research, including meaningful additions to research design, definition of research priorities, and dissemination of outcomes. It is therefore critical that patients and patient advocates be part of the biomedical research process; which can be achieved by changing the perspective of patients as the recipients of research outcomes, to being partners in the process. Patient, clinician, and researcher interactions are particularly important in rare disease research, where little funding is allocated to each disease, making the definition of research priorities even more important. Here, we outline how patients can contribute to biomedical research and provide a step-by-step guide for patient engagement at scientific conferences.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13492564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}