Journal of Biological Chemistry最新文献_第10页

Fast peptide bond formation and release by the ribosomal large subunit. 核糖体大亚基快速肽键形成和释放。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-03 DOI: 10.1016/j.jbc.2025.110336

Letian Bao, Anthony C Forster

{"title":"Fast peptide bond formation and release by the ribosomal large subunit.","authors":"Letian Bao, Anthony C Forster","doi":"10.1016/j.jbc.2025.110336","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110336","url":null,"abstract":"Peptide bond formation and peptidyl release are catalyzed at the peptidyl transferase center (PTC) of the 50S subunit of the 70S ribosome. Proposed catalytic mechanisms at the PTC are based on structures of model substrates bound to the 50S and the 70S. Yet, peptidyl transfer and release reactions catalyzed by the 50S are slower by >3 orders of magnitude than those of the 70S. Here, we obtained a near-physiological rate of peptide bond formation with puromycin catalyzed by the 50S in 33% methanol at 37°C, and fast rates were even attained in aqueous solution using 20% polyethylene glycol (PEG). Interestingly, methanol, not PEG, accelerated the reaction by stimulating substrate binding just to the 50S P site. In addition, we obtained fast peptidyl release model reactions catalyzed by tRNAPhe or CCA trinucleotide on the 50S in 30% acetone. However, PEG did not enable the release reaction, suggesting different mechanisms for release and peptide bond formation. The now-comparable peptidyl transfer rates of the 50S and 70S under aqueous conditions strengthen mechanistic proposals, give credence to hypothetical progenitor ribosomes before evolution of the 30S, and will aid mechanistic investigations with model substrates or ancestral subsets of the ribosome.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110336"},"PeriodicalIF":4.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

USP25 Maintains KRAS Expression and Inhibiting the Deubiquitinase Suppresses KRAS Signaling in Human Cancer. USP25维持KRAS表达，抑制去泛素酶抑制KRAS信号传导

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-03 DOI: 10.1016/j.jbc.2025.110337

Huailu Ma, Huiyuan Guan, Xiao Sun, Lingzhi Wu, Mengjiao Cai, Xinghua Zhen, Xiang Shen, Suxia Han, Guangxue Liu, Jin Peng, Pumin Zhang

引用次数: 0

Tripartite binding mode of cohesin-dockerin complexes from Ruminococcus flavefaciens involving naturally truncated dockerins. 黄瘤球菌黏结蛋白-码头蛋白复合物的三方结合模式，包括自然截断的码头蛋白。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-02 DOI: 10.1016/j.jbc.2025.110325

Marlene Duarte, Ana Luísa Carvalho, Magda C Ferreira, Beatriz Caires, Maria João Romão, José A M Prates, Shabir Najmudin, Edward A Bayer, Carlos Mga Fontes, Pedro Bule

{"title":"Tripartite binding mode of cohesin-dockerin complexes from Ruminococcus flavefaciens involving naturally truncated dockerins.","authors":"Marlene Duarte, Ana Luísa Carvalho, Magda C Ferreira, Beatriz Caires, Maria João Romão, José A M Prates, Shabir Najmudin, Edward A Bayer, Carlos Mga Fontes, Pedro Bule","doi":"10.1016/j.jbc.2025.110325","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110325","url":null,"abstract":"Polysaccharides in plant cell walls serve as a rich carbon and energy source, yet their structural complexity presents a barrier to efficient degradation. To address this, anaerobic microorganisms like Ruminococcus flavefaciens have developed sophisticated multi-enzyme complexes known as cellulosomes, which enable the efficient breakdown of these recalcitrant polysaccharides. These complexes are assembled through high-affinity interactions between cohesin (Coh) modules in scaffoldin proteins and dockerin (Doc) modules in cellulosomal enzymes. R. flavefaciens FD-1 harbours one of the most intricate cellulosomes described to date, comprising over 200 Doc-containing proteins encoded in its genome. Despite substantial research on this cellulosome, the role of a group of truncated but functional dockerins, known as group-2 Docs, remains unclear. In this study, we present a detailed structural and binding analysis of a Coh-Doc complex involving the cohesin from the cell-anchoring scaffoldin ScaE and a group-2 Doc that bears only one of the two Ca+2-coordinating loops that characterise the canonical Docs. Our findings reveal a novel tripartite binding mechanism, in which the cohesin can simultaneously bind two distinct dockerin units in three alternative conformations. This discovery provides new insights into the modular versatility of the R. flavefaciens cellulosome and sheds light on the mechanisms that enhance its efficiency in polysaccharide degradation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110325"},"PeriodicalIF":4.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 molecular basis of T cell receptor recognition of citrullinated tenascin-C presented by HLA-DR4. HLA-DR4提供的瓜氨酸tenascin-C T细胞受体识别的分子基础。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-06-02 DOI: 10.1016/j.jbc.2025.110326

Hien Thy Dao, Tiing Jen Loh, Ravi K Sharma, Lars Klareskog, Vivianne Malmström, Hugh H Reid, Jamie Rossjohn, Jia Jia Lim

{"title":"The molecular basis of T cell receptor recognition of citrullinated tenascin-C presented by HLA-DR4.","authors":"Hien Thy Dao, Tiing Jen Loh, Ravi K Sharma, Lars Klareskog, Vivianne Malmström, Hugh H Reid, Jamie Rossjohn, Jia Jia Lim","doi":"10.1016/j.jbc.2025.110326","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110326","url":null,"abstract":"CD4+ T cell autoreactivity against citrullinated (cit) self-epitopes presented by HLA-DRB1 is associated with rheumatoid arthritis (RA) pathogenesis. We understand the molecular bases of T cell receptor (TCR) recognition of cit-fibrinogen, cit-vimentin, and cit-α-enolase epitopes, and the role of citrulline in shaping TCR repertoire usage. Nevertheless, how TCRs recognise other cit-epitopes, including tenascin-C (TNC) and how alternative citrullination positions may modulate the T cell recognition remains unclear. Here, we examined TNC1014,1016cit peptide, which contains citrullination at position P-1 and P2, to study the underlying TCR-HLA-DRB1*04:01- TNC1014,1016cit molecular interactions. Crystal structure of HLA-DRB1*04:01TNC1014,1016cit at 2.4 Å resolution revealed a conserved peptide binding register to the established HLA-DRB1*04:01-peptide structures, where both citrullines protruded upwards. Next, we determined the crystal structure of a RA patient-derived TRAV35+/TRBV10-2+ (PB) TCR in complex with HLA-DRB1*04:01TNC1014,1016cit at 3.2 Å resolution. The CDR3α loop (109VGNTN113) of PB TCR formed a secondary helical conformation at the N-terminus of the peptide binding cleft, allowing extensive interactions between the P-1 and P2 citrullines of TNC1014,1016cit peptide. Surface plasmon resonance, tetramer staining, and CD69 activation assays revealed that the PB TCR did not cross-react to other RA autoantigens, and the P-1-Cit, P2-Cit, and P5-Tyr of TNC1014,1016cit are the key determinants underlining the strict specificity of the PB TCR. Collectively, we provide molecular insight of citrullination in modulating TCR recognition.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110326"},"PeriodicalIF":4.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Inhibition of sulfotransferase SULT2B1 prevents obesity and insulin resistance by regulating energy expenditure and intestinal lipid absorption. 抑制硫转移酶SULT2B1通过调节能量消耗和肠道脂质吸收来预防肥胖和胰岛素抵抗。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-05-31 DOI: 10.1016/j.jbc.2025.110327

Jingyuan Wang, Gregory Young, Min Zhang, Sonia R Salvatore, Fu-Ying Qin, Xinran Cai, Meishu Xu, Mengyun Ke, Lingyi Liu, Jong-Won Kim, Pengfei Xu, Bin Yang, Songrong Ren, Ye Feng, Da Yang, Xiaochao Ma, Francisco J Schopfer, Wen Xie

{"title":"Inhibition of sulfotransferase SULT2B1 prevents obesity and insulin resistance by regulating energy expenditure and intestinal lipid absorption.","authors":"Jingyuan Wang, Gregory Young, Min Zhang, Sonia R Salvatore, Fu-Ying Qin, Xinran Cai, Meishu Xu, Mengyun Ke, Lingyi Liu, Jong-Won Kim, Pengfei Xu, Bin Yang, Songrong Ren, Ye Feng, Da Yang, Xiaochao Ma, Francisco J Schopfer, Wen Xie","doi":"10.1016/j.jbc.2025.110327","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110327","url":null,"abstract":"Obesity is a major risk factor for multiple metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). The cholesterol sulfotransferase SULT2B1 is best known for its function in converting cholesterol to cholesterol sulfate. Here, by using the high fat diet (HFD)-induced obesity model and the genetic obese ob/ob mice, we showed that genetic ablation of Sult2b1 protected mice from developing obesity and related insulin resistance, hepatic steatosis, and adipose tissue inflammation. Loss of Sult2b1 increased energy expenditure without affecting food intake or locomotive activity. The cold exposure test revealed that loss of Sult2b1 promoted thermogenesis in brown adipose tissue, which may have contributed to increased energy expenditure. In vivo reconstitution experiments suggested that the loss of Sult2b1 in extrahepatic tissues might have been responsible for the metabolic benefit. Mechanistically, our in vivo lipid uptake and metabolomic analyses showed that the Sult2b1KO mice exhibited suppression of intestinal dietary lipid absorption and the consequent downregulation of both systemic fatty acid level and fatty acid metabolism. Our results suggest that targeting SULT2B1 may represent a novel strategy to combat obesity and related metabolic syndrome.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110327"},"PeriodicalIF":4.0,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Perturbations in L-serine metabolism regulates protein quality control through sensor of retrograde response pathway Rtg2 in S.cerevisae. l -丝氨酸代谢的扰动通过逆行反应通路Rtg2传感器调控酿酒酵母蛋白质量控制。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-05-31 DOI: 10.1016/j.jbc.2025.110329

Kanika Saxena, Rebecca Andersson, Per O Widlund, Sakda Khoomrung, Sarah Hanzén, Jens Nielsen, Navinder Kumar, Mikael Molin, Thomas Nyström

{"title":"Perturbations in L-serine metabolism regulates protein quality control through sensor of retrograde response pathway Rtg2 in S.cerevisae.","authors":"Kanika Saxena, Rebecca Andersson, Per O Widlund, Sakda Khoomrung, Sarah Hanzén, Jens Nielsen, Navinder Kumar, Mikael Molin, Thomas Nyström","doi":"10.1016/j.jbc.2025.110329","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110329","url":null,"abstract":"Cellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since, most of these processes are energy driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse and metabolic imbalance are both linked to aging and age-associated disorders, yet they have traditionally been studied as a separate phenomenon in the context of aging. In this study, we indicate that reduced proteostasis capacity is a result of a metabolic imbalance associated with age. We observed increased accumulation of L-serine and L-threonine in replicative old cells of S. cerevisiae, indicating an imbalance in amino acid metabolism with replicative aging. Replicating this metabolic imbalance in young cells through deletion of serine dependent transcriptional activator, CHA4, resulted in increased aggregation of endogenous proteins along with misfolding prone proteins Guk1-7ts-GFP and Luciferase-GFP in both young and old cells. Aggregate formation in the cha4Δ strain required a functional sensor of mitochondrial dysfunction and an activator of the retrograde signalling gene, RTG2. CHA4 and RTG2 exhibited genetic interaction and together regulated mitochondrial metabolism, replicative lifespan, and aggregate formation in young cells, connecting metabolic regulation with proteostasis and aging. Constitutive activation of retrograde signalling through overexpression of RTG2 or deletion of MKS-1, negative regulator of Rtg1-Rtg3 nuclear translocation, resulted in faster resolution of aggregates upon heat shock through RTG3 and was found to be independent of molecular chaperone upregulation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110329"},"PeriodicalIF":4.0,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Targeted removal of the 16S rRNA anti-Shine-Dalgarno sequence by a Mycobacterium tuberculosis MazF toxin. 结核分枝杆菌MazF毒素靶向去除16S rRNA抗shine - dalgarno序列

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-05-30 DOI: 10.1016/j.jbc.2025.110323

Timothy W Sherrier, Valdir C Barth, Jason M Schifano, Julia R Greendyk, Nancy A Woychik

{"title":"Targeted removal of the 16S rRNA anti-Shine-Dalgarno sequence by a Mycobacterium tuberculosis MazF toxin.","authors":"Timothy W Sherrier, Valdir C Barth, Jason M Schifano, Julia R Greendyk, Nancy A Woychik","doi":"10.1016/j.jbc.2025.110323","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110323","url":null,"abstract":"The genome of the bacterial pathogen that causes tuberculosis, Mycobacterium tuberculosis (Mtb), encodes an inexplicably high number of type II toxin-antitoxin (TA) systems. Because this ancient pathogen has evolved to resist clearance by antibiotics and the host immune system, its toxin-antitoxin systems are thought to participate in the survival of these stresses. Of the ∼70 Mtb type II TA systems, 10 MazEF family members have been previously identified, yet the precise cellular target of only one of these MazF toxins is known. Here we demonstrate that the Rv3098A gene encodes an 11th MazF paralog in Mtb (MazF-mt11, MazF11). As with all MazF toxins, MazF-mt11 acts as a single-strand, sequence-specific endoribonuclease. We first performed primer extension on the large single-stranded MS2 enterobacteriophage RNA substrate after incubation with recombinant MazF-mt11 to identify a single toxin cleavage site between C↓A. We then further pinpointed the boundaries of the MazF-mt11 cleavage consensus sequence as C↓ACCU using Escherichia coli MORE RNA-seq. Finally, we enlisted 5'-OH RNA-seq to reveal 16S rRNA in the 30S ribosomal subunit as the only MazF-mt11 RNA target in mycobacteria. In fact, the single cleavage site in C↓ACCU maps just before the anti-Shine-Dalgarno (aSD) at the 3' end of 16S rRNA. Targeted removal of the aSD by MazF-mt11 leads to nearly complete inhibition of protein synthesis, consistent with its important role in directing ribosomes to translation start codons in leadered mRNAs. The accompanying growth arrest phenotype suggests that MazF-mt11 may participate in establishment of the nonreplicating persistent state in Mtb.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110323"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Molecular Insights into Chemotherapy Resistance Mediated by MLL-AF9 Fusion Gene in Pediatric B-Cell Acute Lymphoblastic Leukemia. MLL-AF9融合基因介导儿童b细胞急性淋巴细胞白血病化疗耐药的分子机制研究

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-05-30 DOI: 10.1016/j.jbc.2025.110321

Xu Sang, Yanchun Guan, Mengying Jiang, Xin Chen, Zhen Zhang, Wansheng Peng, Yumeng Wu

{"title":"Molecular Insights into Chemotherapy Resistance Mediated by MLL-AF9 Fusion Gene in Pediatric B-Cell Acute Lymphoblastic Leukemia.","authors":"Xu Sang, Yanchun Guan, Mengying Jiang, Xin Chen, Zhen Zhang, Wansheng Peng, Yumeng Wu","doi":"10.1016/j.jbc.2025.110321","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110321","url":null,"abstract":"This research utilized multi-omics data to elucidate the molecular mechanisms of chemotherapy resistance in pediatric B-cell acute lymphoblastic leukemia (B-ALL) driven by the MLL-AF9 fusion gene. Transcriptome data from B-ALL patients in the Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases were analyzed using weighted gene co-expression network analysis (WGCNA), identifying IGFBP7 as a critical gene associated with MLL-AF9 rearrangement. The MLL-AF9 fusion upregulated IGFBP7, activating ABCB1 transporters and the DNA-PKcs-mediated non-homologous end-joining (NHEJ) repair pathway, thereby promoting chemoresistance. In vitro experiments demonstrated that MLL-AF9-overexpressing B-ALL cells exhibited reduced sensitivity to doxorubicin (DOX), cyclophosphamide (CTX), and cisplatin (DDP). Proteomic and functional assays confirmed elevated ABCB1 and DNA-PKcs expression in MLL-AF9 positive cells, enhancing DNA repair and suppressing apoptosis. Chemoresistance was effectively reversed by the ABC transporter inhibitor Verapamil and the NHEJ inhibitor NU7441 in in vitro and in vivo models. These findings highlight MLL-AF9's role in mediating chemoresistance via ABCB1 and the NHEJ pathways, offering potential therapeutic targets for MLL-AF9-positive B-ALL.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110321"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis. 转录因子HOXA9诱导染色质修饰因子SMYD3的表达来驱动白血病的发生。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-05-30 DOI: 10.1016/j.jbc.2025.110320

Liping Zhang, Jinqiu Zhong, Luo Yang, Qianyun Ye, Yanli Jin, Chang Liu, Peilong Lai, Hongle Li, Jingxuan Pan, Bei Jin

{"title":"The transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis.","authors":"Liping Zhang, Jinqiu Zhong, Luo Yang, Qianyun Ye, Yanli Jin, Chang Liu, Peilong Lai, Hongle Li, Jingxuan Pan, Bei Jin","doi":"10.1016/j.jbc.2025.110320","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110320","url":null,"abstract":"Fusion oncogene MLL-AF9 initiates AML via downstream targets such as HOXA9. Drivers in the complicated settings of advanced AML, however, remain to be incompletely elucidated. Any factors to incur upregulation of the effector HOXA9 predictably aggravate the effect of DOT1L-mediated H3K79 methylation on HOXA9 expression in MLL-AF9-driven AML. In the present study, we identified that SET and MYND domain-containing protein 3 (SMYD3) was overexpressed in AML and predicted a poor prognosis for AML patients. Given that H3K4me3 typically activates the transcription of oncogenes, we hypothesized that SMYD3-catalyzed H3K4me3 may directly increase HOXA9 transcription, offering an additional regulation layer to HOXA9 gene transcription activation in MLL-AF9 AML. We tested this hypothesis and unveiled that SMYD3 is responsible for mediating H3K4me3 enrichment and for independently activating HOXA9 transcription. Transcription factor HOXA9 in turn bound to the promoter region of SMYD3 and enhanced its transcription. The resultant vicious circle of SMYD3-H3K4me3-HOXA9 exacerbated proliferation and blocked differentiation in both AML cell lines and primary cells fractionated from patients with AML. Combinational disruption of this loop and DOT1L inhibition led to enhanced anti-leukemia activity against MLL-AF9 AML in vitro and in vivo. In conclusion, our findings may advocate the current understanding regarding the underlying mechanism and offer SMYD3 as a promising intervention target to override the complicated settings in advanced AML.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110320"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Orthologues of the human protein histidine methyltransferase METTL9 display distinct substrate specificities. 人蛋白组氨酸甲基转移酶METTL9的同源物显示出不同的底物特异性。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-05-30 DOI: 10.1016/j.jbc.2025.110318

Lisa Schroer, Sara Weirich, Marta Hammerstad, Hans-Petter Hersleth, Ida Andrietta Grønsberg, Lars Hagen, Geir Slupphaug, Jedrzej Mieczyslaw Malecki, Albert Jeltsch, Pål Ø Falnes, Erna Davydova

{"title":"Orthologues of the human protein histidine methyltransferase METTL9 display distinct substrate specificities.","authors":"Lisa Schroer, Sara Weirich, Marta Hammerstad, Hans-Petter Hersleth, Ida Andrietta Grønsberg, Lars Hagen, Geir Slupphaug, Jedrzej Mieczyslaw Malecki, Albert Jeltsch, Pål Ø Falnes, Erna Davydova","doi":"10.1016/j.jbc.2025.110318","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110318","url":null,"abstract":"The human (Homo sapiens; Hs) methyltransferase (MTase) METTL9 is the first enzyme shown to generate 1-methylhistidine (π-methylhistidine) in proteins. METTL9 preferentially methylates an alternating histidine (HxH) motif, where \"x\" is a small, uncharged amino acid, and multiple substrates have been identified. Putative METTL9 orthologues are found in most eukaryotes, and we have here investigated the activity of such enzymes from several species, representing all five eukaryotic supergroups. The majority of the tested enzymes demonstrated in vitro MTase activity on the prototype HsMETTL9 substrates ARMC6 and DNAJB12. We also detected protein methylation activity of the Caenorhabditis elegans METTL9 which had previously been suggested to be a DNA MTase. However, METTL9 from the fruit fly (Drosophila melanogaster) and the picoplankton Ostreococcus tauri (Ot) displayed distinct substrate specificities, differing from each other and from that of HsMETTL9. These differences were observed when recombinant proteins and short peptides were used as METTL9 substrates. To further analyze substrate specificity, we used peptide arrays to systematically replace the \"x\" residue and the residues flanking the HxH motif in a substrate peptide. This revealed varying degrees of tolerance among the METTL9 orthologues (Hs > Dm > Ot) for substitutions at these positions. Our results show that the METTL9 orthologues, although requiring an HxH target site, have evolved different substrate specificities, likely due to differing biologically relevant substrates in the respective organisms. Furthermore, we solved the X-ray structure of OtMETTL9, revealing several differences from the previously published HsMETTL9 structures that may explain its distinct substrate specificity.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110318"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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