FEBS Letters最新文献

{"title":"Thermodynamic versus kinetic basis for the high conformational stability of nanobodies for therapeutic applications.","authors":"Atanasio Gómez-Mulas, Mario Cano-Muñoz, Eduardo Salido Ruiz, Angel Luis Pey","doi":"10.1002/1873-3468.15064","DOIUrl":"https://doi.org/10.1002/1873-3468.15064","url":null,"abstract":"<p><p>Nanobodies (NB) are powerful tools for biotechnological and therapeutic applications. They strongly bind to their targets and are very stable. Early studies showed that NB unfolding is reversible and can be analyzed by equilibrium thermodynamics, whereas more recent studies focused on their kinetic stability in very harsh conditions that are far from storage or physiological temperatures (4-37 °C). Here, we show that the thermodynamic view of NB stability holds in a wide range of temperatures (18-100 °C). The thermodynamic stability of three different NBs did not correlate with binding affinity for their target. Alpha-Fold 2 analyses of these NBs showed structural differences in the binding site and hydrogen bond networks. We expect that our approach will be helpful to improve our capacity to enhance structure-function-stability relationships of NB.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727401","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":"Clues to transcription/replication collision-induced DNA damage: it was RNAP, in the chromosome, with the fork.","authors":"Matthew B Cooke, Christophe Herman, Priya Sivaramakrishnan","doi":"10.1002/1873-3468.15063","DOIUrl":"https://doi.org/10.1002/1873-3468.15063","url":null,"abstract":"<p><p>DNA replication and RNA transcription processes compete for the same DNA template and, thus, frequently collide. These transcription-replication collisions are thought to lead to genomic instability, which places a selective pressure on organisms to avoid them. Here, we review the predisposing causes, molecular mechanisms, and downstream consequences of transcription-replication collisions (TRCs) with a strong emphasis on prokaryotic model systems, before contrasting prokaryotic findings with cases in eukaryotic systems. Current research points to genomic structure as the primary determinant of steady-state TRC levels and RNA polymerase regulation as the primary inducer of excess TRCs. We review the proposed mechanisms of TRC-induced DNA damage, attempting to clarify their mechanistic requirements. Finally, we discuss what drives genomes to select against TRCs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709688","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":"'Friend versus foe'-does autophagy help regulate symbiotic plant-microbe interactions and can it be manipulated to improve legume cultivation?","authors":"Nipuni Thanthrige, Sudipta Das Bhowmik, Brett Williams","doi":"10.1002/1873-3468.15062","DOIUrl":"https://doi.org/10.1002/1873-3468.15062","url":null,"abstract":"<p><p>Autophagy is a genetically regulated, eukaryotic catabolic pathway that responds to internal and external cellular signals. In plants, it plays crucial roles in development, and responses to abiotic and biotic stresses. Due to its role in limiting the hypersensitive response, research on the molecular mechanisms of autophagic signalling pathways in plant-microbe interactions has primarily focused on plant-pathogen responses. Although there is substantially less information on the role of autophagy signalling in symbiotic plant-microbe interactions, there is accumulating evidence that it is also a key regulator of mutualistic plant-microbe interactions. Here, we review recent progress on the roles of autophagy in symbiotic plant interactions and discuss potential future research directions. Once understood, the central role that autophagy plays within pathogenic and symbiotic plant-microbe interactions has significant potential application for crop improvement. Manipulating autophagy in legume crops could help support crop growth with reduced levels of fertiliser application while maintaining yields with increased protein content in the harvest.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709693","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":"Molecular and cellular pathways of aging in hematopoiesis","authors":"Eleni Katsantoni","doi":"10.1002/1873-3468.15049","DOIUrl":"https://doi.org/10.1002/1873-3468.15049","url":null,"abstract":"&lt;p&gt;Aging is defined as the time-related downgrade of the functions of an organism necessary for survival and fertility. Both genetic and environmental factors influence aging, which involves several cellular and molecular changes occurring in cells, tissues, and the whole organism. In vertebrates, the process of aging begins at conception and extends to the continuum of all life stages, up to the geriatric one.&lt;/p&gt;&lt;p&gt;Increased life expectancy is one of humanity's greatest achievements. The elderly population has increased in the last few decades due to scientific and technological advancements that have improved living conditions and have led to efficient therapeutic management of age-related disorders. By 2050, the population over 60 years of age is expected to double worldwide [&lt;span&gt;[1]&lt;/span&gt;]. Despite the scientific accomplishments in aging research, globally many elderly people still find themselves in unsupportive environments. To address this need, various initiatives have been implemented to help the rapidly growing number of aged persons to be healthy and contribute to their families and societies. The Healthy Ageing Collaborative of the World Health Organization aims to improve the lives of the elderly, support the implementation of the United Nations Decade of Healthy Ageing (2021–2030) and other related initiatives, strengthen international collaboration on healthy aging, and recognize the role of older individuals. The Decade of Healthy Ageing focuses on developing age-friendly environments and improving healthcare systems. Under these initiatives, aging-related research is a priority [&lt;span&gt;[2]&lt;/span&gt;], and various challenges linked to the molecular understanding, prognosis, diagnosis, and therapeutic management of age-related disorders, including the hematological ones [&lt;span&gt;[3-5]&lt;/span&gt;], need to be addressed. In line with this direction, this Special Issue focuses on aging-related research in hematopoiesis.&lt;/p&gt;&lt;p&gt;Basic research in the last few decades has contributed to our understanding of the molecular mechanisms of aging. Various interconnected hallmarks of aging have been defined, including genomic instability, telomere attrition, cellular senescence, stem cell exhaustion, chronic inflammation, dysbiosis, and alterations/deregulation in the epigenome, proteostasis, macroautophagy, nutrient-sensing, mitochondrial function, and intercellular communication [&lt;span&gt;[6]&lt;/span&gt;]. These hallmarks are also observed in cells of the hematopoietic system including hematopoietic stem cells (HSCs), offering multiple opportunities to reverse aging by therapeutically modifying the associated cellular processes and pathways.&lt;/p&gt;&lt;p&gt;As humans age, multiple changes occur in the bone marrow, leading to hematological disorders, including cytopenias, defects in immune responses, and hematologic malignancies [&lt;span&gt;[7]&lt;/span&gt;]. HSCs ensure a balanced production of all blood cell lineages throughout life. Upon aging, HSCs gradually lose their self-","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"598 22","pages":"2751-2754"},"PeriodicalIF":3.5,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.15049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708178","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":"Transcriptomic insights into the virulence of Acinetobacter baumannii during infection-role of iron uptake and siderophore production genes.","authors":"Kah Ern Ten, Sadequr Rahman, Hock Siew Tan","doi":"10.1002/1873-3468.15061","DOIUrl":"https://doi.org/10.1002/1873-3468.15061","url":null,"abstract":"<p><p>Acinetobacter baumannii, a top-priority WHO pathogen, causes life-threatening infections in immunocompromised patients, leading to prolonged hospitalisation and high mortality. Here, we used the Galleria mellonella model to investigate community strain C98 (Ab-C98) virulence via transcriptomic analysis. Ab-C98 showed greater killing and faster colonisation in larvae than the clinical reference strain (ATCC BAA1605). Genes in three iron clusters, acinetobactin, baumannoferrin and the Feo system, were significantly up-regulated. Targeted knockout of siderophore genes (basC, bfnD, and the gene encoding isochorismatase) significantly increased the survival of infected larvae by at least 35.16%, identifying these genes as potential targets for developing anti-virulence agents against A. baumannii.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686343","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":"Disruption of Iqsec1 in mice leads to embryonic lethality with reduced large apical vacuoles in the visceral endoderm.","authors":"Hiroyuki Sakagami, Tomoko Shiroshima, Noriko Nemoto, Tomoko Niimura, Takeyuki Sugawara, Yoshinobu Hara, Koji Saito, Tadashi Okubo, Masahiro Fukaya","doi":"10.1002/1873-3468.15058","DOIUrl":"https://doi.org/10.1002/1873-3468.15058","url":null,"abstract":"<p><p>Iqsec1 (IQ motif and Sec7 domain-containing protein 1), also known as BRAG2 (Brefeldin A-resistant Arf-GEF 2), is a guanine nucleotide exchange factor that regulates membrane trafficking, cytoskeletal organization, and signal transduction by activating class II and III ADP-ribosylation factors. To investigate the physiological role of Iqsec1 at the whole animal level, we generated Iqsec1-deficient mice using CRISPR/Cas9-mediated gene editing. Nearly all Iqsec1^-/- mice (99%) exhibited embryonic lethality with severe growth retardation. Electron microscopy revealed that Iqsec1^-/- embryos at embryonic day 8.5 lacked large apical vacuoles in visceral endoderm cells of the yolk sac, compared with controls. These findings suggest that Iqsec1 plays a critical role in embryogenesis, likely through regulation of membrane trafficking in visceral endoderm cells.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675437","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":"FBXO46 negatively regulates p53 activity by stabilizing Mdm2.","authors":"Lai Wei, Ning Yu, Bo Yao, Yide Mei, Kailiang Zhao","doi":"10.1002/1873-3468.15055","DOIUrl":"https://doi.org/10.1002/1873-3468.15055","url":null,"abstract":"<p><p>The tumor suppressor p53 plays a central role in suppressing tumor formation. Mouse double minute 2 homolog (Mdm2) serves as the principal ubiquitin E3 ligase responsible for the ubiquitination and subsequent degradation of p53. However, the regulatory mechanisms governing the Mdm2-p53 pathway are not comprehensively understood. Here, we report that F-box only protein 46 (FBXO46) directly binds to Mdm2 and inhibits its self-ubiquitination and degradation, leading to Mdm2 stabilization and subsequent Mdm2-mediated ubiquitination and degradation of p53. Functionally, FBXO46 promotes cell proliferation, accelerates G1/S cell cycle progression, and increases anchorage-independent cell growth by inhibiting p53. Collectively, these findings reveal a critical role for FBXO46 in controlling Mdm2 stability and establish FBXO46 as an important regulator of the Mdm2-p53 pathway.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644302","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":"The E3 ligase HUWE1 interacts with ubiquitin non-covalently via key residues in the HECT domain.","authors":"Li Sun, Haoran Zhang, Yan Li","doi":"10.1002/1873-3468.15050","DOIUrl":"https://doi.org/10.1002/1873-3468.15050","url":null,"abstract":"<p><p>HUWE1, a HECT E3 ligase, is critical for processes like protein degradation and tumor development. Contrary to previous findings which suggested minimal non-covalent interactions between the HUWE1 HECT domain and ubiquitin, we identified a non-covalent interaction between the HUWE1 HECT N-lobe and ubiquitin using NMR spectroscopy, revealing a conserved ubiquitin-binding mode shared across HECT E3 ligases. Molecular dynamics simulations not only confirmed the stability of this interaction but also uncovered conformational changes in key residues, which likely influence binding affinity. Additionally, we highlighted the roles of both conserved and unique residues in ubiquitin binding. These findings advance our understanding of the interactions between the HUWE1 HECT domain and ubiquitin, and highlight potential targets for therapeutic intervention in the ubiquitin-proteasome pathway.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617513","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":"Crystal structure of β-d-galactofuranosidase from Streptomyces sp. JHA19 in complex with an inhibitor provides insights into substrate specificity.","authors":"Noriki Fujio, Chihaya Yamada, Toma Kashima, Emiko Matsunaga, Robert J Nash, Kaoru Takegawa, Shinya Fushinobu","doi":"10.1002/1873-3468.15056","DOIUrl":"https://doi.org/10.1002/1873-3468.15056","url":null,"abstract":"<p><p>d-Galactofuranose (Galf) is widely distributed in glycoconjugates of pathogenic microbes. β-d-Galactofuranosidase (Galf-ase) from Streptomyces sp. JHA19 (ORF1110) belongs to glycoside hydrolase (GH) family 2 and is the first identified Galf-specific degradation enzyme. Here, the crystal structure of ORF1110 in complex with a mechanism-based potent inhibitor, d-iminogalactitol (K_i = 65 μm) was solved. ORF1110 binds to the C5-C6 hydroxy groups of d-iminogalactitol with an extensive and integral hydrogen bond network, a key interaction that discriminates the substrates. The active site structure of ORF1110 is largely different from those of β-glucuronidases and β-galactosidases in the same GH2 family. A C-terminal domain of ORF1110 is predicted to be a carbohydrate-binding module family 42 that may bind Galf. The structural insights into Galf-ase will contribute to the investigation of therapeutic tools against pathogens.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617494","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":"High-throughput detection of RNA modifications at single base resolution.","authors":"Keren Ron, Joshua Kahn, Nofar Malka-Tunitsky, Aldema Sas-Chen","doi":"10.1002/1873-3468.15052","DOIUrl":"10.1002/1873-3468.15052","url":null,"abstract":"<p><p>RNA is modified by > 170 chemical modifications that affect its structure and function. Accordingly, RNA modifications have been implicated in regulation of gene expression and cellular outcomes in a variety of species spanning the phylogenetic tree. The study of RNA modifications is accelerated by generation of high-throughput methods for detecting RNA modifications at single base resolution. Here, we review recent advancement in next generation sequencing based approaches for detection of 14 distinct RNA modifications present in rRNA, tRNA and mRNA. We further outline the molecular and computational principles underlying currently available methods.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617506","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}