{"title":"Cryo-EM structures of the zinc transporters ZnT3 and ZnT4 provide insights into their transport mechanisms.","authors":"Hanako Ishida, Riri Yo, Zhikuan Zhang, Toshiyuki Shimizu, Umeharu Ohto","doi":"10.1002/1873-3468.15047","DOIUrl":"https://doi.org/10.1002/1873-3468.15047","url":null,"abstract":"<p><p>Zinc transporters (ZnTs) act as H<sup>+</sup>/Zn<sup>2+</sup> antiporters, crucial for zinc homeostasis. Brain-specific ZnT3 expressed in synaptic vesicles transports Zn<sup>2+</sup> from the cytosol into vesicles and is essential for neurotransmission, with ZnT3 dysfunction associated with neurological disorders. Ubiquitously expressed ZnT4 localized to lysosomes facilitates the Zn<sup>2+</sup> efflux from the cytosol to lysosomes, mitigating the cell injury risk. Despite their importance, the structures and Zn<sup>2+</sup> transport mechanisms remain unclear. We characterized the three-dimensional structures of human ZnT3 (inward-facing) and ZnT4 (outward-facing) using cryo-electron microscopy. By combining these structures, we assessed the conformational changes that could occur within the transmembrane domain during Zn<sup>2+</sup> transport. Our results provide a structural basis for a more comprehensive understanding of the H<sup>+</sup>/Zn<sup>2+</sup> exchange mechanisms exhibited by ZnTs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544628","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}
FEBS LettersPub Date : 2024-10-27DOI: 10.1002/1873-3468.15040
Jigneshkumar A Mochi, Jaykumar Jani, Smit Shah, Anju Pappachan
{"title":"Leishmania donovani adenylosuccinate synthetase requires IMP for dimerization and organization of the active site.","authors":"Jigneshkumar A Mochi, Jaykumar Jani, Smit Shah, Anju Pappachan","doi":"10.1002/1873-3468.15040","DOIUrl":"https://doi.org/10.1002/1873-3468.15040","url":null,"abstract":"<p><p>Adenylosuccinate synthetase (AdSS), which catalyses the GTP-dependent conversion of inosine monophosphate (IMP) and aspartic acid to succinyl-AMP, plays a major role in purine biosynthesis. In some bacterial AdSS, it is implicated that IMP binding is important to organize the active site, but in certain plant AdSS, GTP performs this role. Here, we report that in Leishmania donovani AdSS, IMP binding favoured dimerization, induced greater conformational change and improved the protein stability more than GTP binding. IMP binding, which resulted in a network of hydrogen bonds, stabilized the conformation of active site loops and brought the switch loop to a closed conformation, which then facilitated GTP binding. Our results provide a basis for designing better inhibitors of leishmanial AdSS.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497593","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}
FEBS LettersPub Date : 2024-10-27DOI: 10.1002/1873-3468.15036
Anqi Dong, Masao Yoshizumi, Hiroki Kokubo
{"title":"Odz4 upregulates SAN-specific genes to promote differentiation into cardiac pacemaker-like cells.","authors":"Anqi Dong, Masao Yoshizumi, Hiroki Kokubo","doi":"10.1002/1873-3468.15036","DOIUrl":"https://doi.org/10.1002/1873-3468.15036","url":null,"abstract":"<p><p>Cardiac arrhythmias stemming from abnormal sinoatrial node (SAN) function can lead to sudden death. Developing a biological pacemaker device for treating sick sinus syndrome (SSS) could offer a potential cure. Understanding SAN differentiation is crucial, yet its regulatory mechanism remains unclear. We reanalyzed published RNA-seq data and identified Odz4 as a SAN-specific candidate. In situ hybridization revealed Odz4 expression in the cardiac crescent and throughout the cardiac conduction system (CCS). To assess the role of Odz4 in CCS differentiation, we utilized a Tet-Off inducible system for its intracellular domain (ICD). Embryonic bodies (EBs) exogenously expressing Odz4-ICD exhibited an increased propensity to develop into pacemaker-like cells with enhanced automaticity and upregulated expression of SAN-specific genes. CellChat and GO analyses unveiled SAN-specific enrichment of ligand-receptor sets, especially Ptn-Ncl, and extracellular matrix components in the group exogenously expressing Odz4-ICD. Our findings underscore the significance of Odz4 in SAN development and offer fresh insights into biological pacemaker establishment.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497669","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}
FEBS LettersPub Date : 2024-10-24DOI: 10.1002/1873-3468.15045
Barnava Banerjee, Chinmay K Kamale, Abhishek B Suryawanshi, Subrata Dasgupta, Santosh Noronha, Prasenjit Bhaumik
{"title":"Crystal structures of Aspergillus oryzae exo-β-(1,3)-glucanase reveal insights into oligosaccharide binding, recognition, and hydrolysis.","authors":"Barnava Banerjee, Chinmay K Kamale, Abhishek B Suryawanshi, Subrata Dasgupta, Santosh Noronha, Prasenjit Bhaumik","doi":"10.1002/1873-3468.15045","DOIUrl":"https://doi.org/10.1002/1873-3468.15045","url":null,"abstract":"<p><p>Exo-β-(1,3)-glucanases are promising enzymes for use in the biofuel industry as they hydrolyse sugars such as laminarin, a major constituent of the algal cell wall. This study reports structural and biochemical characterizations of Aspergillus oryzae exo-β-(1,3)-glucanase (AoBgl) belonging to the GH5 family. Purified AoBgl hydrolyses β-(1,3)-glycosidic linkages of the oligosaccharide laminaritriose and the polysaccharide laminarin effectively. We have determined three high-resolution structures of AoBgl: (a) the apo form at 1.75 Å, (b) the complexed form with bound cellobiose at 1.73 Å and (c) the glucose-bound form at 1.20 Å. The crystal structures, molecular dynamics simulation studies and site-directed mutagenesis reveal the mode of substrate binding and interactions at the active site. The results also indicate that AoBgl effectively hydrolyses trisaccharides and higher oligosaccharides. The findings from our structural and biochemical studies would aid in rational engineering efforts to generate superior AoBgl variants and similar GH5 enzymes for their industrial use.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497592","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}
FEBS LettersPub Date : 2024-10-24DOI: 10.1002/1873-3468.15044
{"title":"RETRACTION: Role of the PDK1-PKB-GSK3 Pathway in Regulating Glycogen Synthase and Glucose Uptake in the Heart.","authors":"","doi":"10.1002/1873-3468.15044","DOIUrl":"https://doi.org/10.1002/1873-3468.15044","url":null,"abstract":"<p><strong>Retraction: </strong>A. Mora, K. Sakamoto, E. J. McManus, and D. R. Alessi, \"Role of the PDK1-PKB-GSK3 Pathway in Regulating Glycogen Synthase and Glucose Uptake in the Heart,\" FEBS Letters 579, no. 17 (2005): 3632-3638, https://doi.org/10.1016/j.febslet.2005.05.040. The above article, published online on 06 June 2005 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Michael Brunner; FEBS Press; and John Wiley and Sons Ltd. The journal was contacted by a representative of the research integrity group at the authors' institute, since an institutional investigation revealed inappropriate splicing and duplication of image sections within Fig. 2A, B and Fig. 3A. Consequently, the conclusions of the paper are substantially compromised, and the institute has recommended the paper to be retracted. The editors of the journal agree with the retraction based on the institutional investigation.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497670","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}
FEBS LettersPub Date : 2024-10-24DOI: 10.1002/1873-3468.15042
Kai Rogge, Tobias Johannes Wagner, Dirk Hoffmeister, Bernhard Rupp, Sebastiaan Werten
{"title":"Substrate recognition by the 4-hydroxytryptamine kinase PsiK in psilocybin biosynthesis.","authors":"Kai Rogge, Tobias Johannes Wagner, Dirk Hoffmeister, Bernhard Rupp, Sebastiaan Werten","doi":"10.1002/1873-3468.15042","DOIUrl":"https://doi.org/10.1002/1873-3468.15042","url":null,"abstract":"<p><p>Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l-tryptophan involves four strictly sequential modifications. The third of these, ATP-dependent phosphorylation of the intermediate 4-hydroxytryptamine, is catalysed by PsiK. Here we present a crystallographic analysis and a structure-based mutagenesis study of this kinase, providing insight into its mode of substrate recognition. The results of our work will support future bioengineering efforts aimed at generating variants of psilocybin with enhanced therapeutic properties.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497671","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}
{"title":"Mapping the sclerostin-LRP4 binding interface identifies critical interaction hotspots in loops 1 and 3 of sclerostin.","authors":"Svetlana Katchkovsky, Reut Meiri, Shiran Lacham-Hartman, Yaron Orenstein, Noam Levaot, Niv Papo","doi":"10.1002/1873-3468.15033","DOIUrl":"https://doi.org/10.1002/1873-3468.15033","url":null,"abstract":"<p><p>The interaction of sclerostin (Scl) with the low-density lipoprotein receptor-related protein 4 (LRP4) leads to a marked reduction in bone formation by inhibiting the Wnt/β-catenin pathway. To characterize the Scl-LRP4 binding interface, we sorted a combinatorial library of Scl variants and isolated variants with reduced affinity to LRP4. We identified Scl single-mutation variants enriched during the sorting process and verified their reduction in affinity toward LRP4-a reduction that was not a result of changes in the variants' secondary structure or stability. We found that Scl positions K75 (loop 1) and V136 (loop 3) are critical hotspots for binding to LRP4. Our findings establish the foundation for targeting these hotspots for developing novel therapeutic strategies to promote bone formation.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497594","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}
FEBS LettersPub Date : 2024-10-22DOI: 10.1002/1873-3468.15041
Laura A Novotny, Eric G Meissner
{"title":"Expression and function of interferon lambda receptor 1 variants.","authors":"Laura A Novotny, Eric G Meissner","doi":"10.1002/1873-3468.15041","DOIUrl":"10.1002/1873-3468.15041","url":null,"abstract":"<p><p>Lambda interferons (IFNLs) provide critical host defense against pathogens encountered at mucosal surfaces. In humans, IFNL signaling is regulated in part by low and cell-type restricted expression of the lambda interferon receptor 1 protein with expression restricted primarily to epithelial cells located at mucosal surfaces. This review will examine the evidence suggesting a role for IFNLR1 transcriptional variants in mediating cell responsiveness to IFNL ligand exposure and regulation of pathway activity.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461343","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}
FEBS LettersPub Date : 2024-10-20DOI: 10.1002/1873-3468.15043
Roy D Sleator
{"title":"Solving the protein folding problem….","authors":"Roy D Sleator","doi":"10.1002/1873-3468.15043","DOIUrl":"https://doi.org/10.1002/1873-3468.15043","url":null,"abstract":"<p><p>The protein folding problem was, to paraphrase Churchill, 'A riddle wrapped in a mystery inside an enigma'. The riddle, in this context, was the folding code; what interactions at the amino acid level are driving the folding process? The mystery was the kinetic question (Levinthal's paradox); how does the folding process occur so quickly (typically in timescales ranging from μS to mS)? Finally, the enigma represents the computational problem of developing approaches to predict the final folded sate of a protein given only its amino acid sequence. Herein, I trace the path to solving this riddle wrapped in a mystery inside an enigma.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461346","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}
FEBS LettersPub Date : 2024-10-20DOI: 10.1002/1873-3468.15034
Jin Lei, Xue-Wei Cao, Peng-Fei Li, Jian Zhao, Fu-Jun Wang
{"title":"Platycodin D reduces PD-L1 levels by inhibiting LXR-β activity and combines with nintedanib to enhance the tumor-killing effect of T cells.","authors":"Jin Lei, Xue-Wei Cao, Peng-Fei Li, Jian Zhao, Fu-Jun Wang","doi":"10.1002/1873-3468.15034","DOIUrl":"https://doi.org/10.1002/1873-3468.15034","url":null,"abstract":"<p><p>Most tumors are resistant to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors, which may be due to impaired antigen presentation resulting from the downregulation of major histocompatibility complex class I (MHC-I) expression on tumor cells. We observed that platycodin D (PD), polygalacin D, and platycodin D2, which are plant-derived triterpenoid saponins, significantly reduced PD-L1 levels. RNA sequencing and the PharmMapper database analysis identified liver X receptor β (LXR-β) as a potential PD target. Further studies showed that PD reduces PD-L1 levels by binding to LXR-β and inhibiting LXR-β activity. Coadministration of PD and nintedanib, known to upregulate MHC-I expression, enhanced tumor recognition and killing by T cells. This study provides new insights into PD applications and mechanisms.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461345","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}