Pub Date : 2024-11-07DOI: 10.1016/j.str.2024.10.017
Wang Xu, Yang Han, Maolin Lu
In this issue of Structure, Dey et al.1 employ single-molecule FRET to map the conformational trajectory of Omicron spikes during fusion, revealing a transition from pre-fusion to post-fusion through two intermediates. This study highlights the roles of acidic environments, Ca2+, and receptors in promoting SARS-CoV-2 cell entry.
{"title":"Multi-step shapeshifting of SARS-CoV-2 Omicron spikes during fusion","authors":"Wang Xu, Yang Han, Maolin Lu","doi":"10.1016/j.str.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.017","url":null,"abstract":"In this issue of <em>Structure</em>, Dey et al.<span><span><sup>1</sup></span></span> employ single-molecule FRET to map the conformational trajectory of Omicron spikes during fusion, revealing a transition from pre-fusion to post-fusion through two intermediates. This study highlights the roles of acidic environments, Ca<sup>2+</sup>, and receptors in promoting SARS-CoV-2 cell entry.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"13 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596478","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}
Pub Date : 2024-11-07DOI: 10.1016/j.str.2024.10.006
Taku Mizutani, Ikuro Abe
The enzymatically regioselective catalyzed incorporation of cysteine sulfoxide into histidine generates physiologically important antioxidants such as ergothioneine and ovothiol. In this issue of Structure, Ireland et al.1 report the crystal structure of EgtB-IV, which provides insights into the convergent evolution of sulfoxide synthase.
{"title":"Traces of convergent evolution left in the structure of EgtB-IV","authors":"Taku Mizutani, Ikuro Abe","doi":"10.1016/j.str.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.006","url":null,"abstract":"The enzymatically regioselective catalyzed incorporation of cysteine sulfoxide into histidine generates physiologically important antioxidants such as ergothioneine and ovothiol. In this issue of <em>Structure</em>, Ireland et al.<span><span><sup>1</sup></span></span> report the crystal structure of EgtB-IV, which provides insights into the convergent evolution of sulfoxide synthase.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"9 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596476","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}
Pub Date : 2024-11-07DOI: 10.1016/j.str.2024.10.010
Qingtong Zhou, Xiao Liu, Ming-Wei Wang
In this issue of Structure, Shaw et al.1 visualize the PI4KA-TTC7B-FAM126A-calcineurin complex by combining cryo-EM, HDX-MS, and AlphaFold3, and reveal a dual interaction of calcineurin with PI4KA and FAM126A. This work promotes our understanding of calcineurin-regulated PI4KA activity and paves the way for further exploration of the roles of PI4KA in the plasma membrane.
{"title":"Visualizing the dual interaction of calcineurin with PI4KA and FAM126A","authors":"Qingtong Zhou, Xiao Liu, Ming-Wei Wang","doi":"10.1016/j.str.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.010","url":null,"abstract":"In this issue of <em>Structure</em>, Shaw et al.<span><span><sup>1</sup></span></span> visualize the PI4KA-TTC7B-FAM126A-calcineurin complex by combining cryo-EM, HDX-MS, and AlphaFold3, and reveal a dual interaction of calcineurin with PI4KA and FAM126A. This work promotes our understanding of calcineurin-regulated PI4KA activity and paves the way for further exploration of the roles of PI4KA in the plasma membrane.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"18 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598266","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}
Pub Date : 2024-11-07DOI: 10.1016/j.str.2024.10.007
Rosemary J. Cater, Renae M. Ryan, Jonathan S. Oakhill, Peter Czabotar, James M. Murphy, Melissa J. Call
Since 1976, the Lorne Proteins Conference has been a key gathering for protein scientists, combining cutting-edge research with community engagement in a picturesque corner of the world. Renowned for its diverse international speakers and collaborative spirit, the conference looks forward to its 50th anniversary in 2025.
{"title":"Structure, function, surf, repeat: A week at Lorne Proteins 2024","authors":"Rosemary J. Cater, Renae M. Ryan, Jonathan S. Oakhill, Peter Czabotar, James M. Murphy, Melissa J. Call","doi":"10.1016/j.str.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.007","url":null,"abstract":"Since 1976, the Lorne Proteins Conference has been a key gathering for protein scientists, combining cutting-edge research with community engagement in a picturesque corner of the world. Renowned for its diverse international speakers and collaborative spirit, the conference looks forward to its 50<sup>th</sup> anniversary in 2025.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"4 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596475","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}
Pub Date : 2024-11-06DOI: 10.1016/j.str.2024.10.009
Rawia Hamid, Danica J. Walsh, Eleonora Diamanti, Diana Aguilar, Antoine Lacour, Mostafa M. Hamed, Anna K.H. Hirsch
Enzymes of the methylerythritol phosphate (MEP) pathway are potential targets for antimicrobial drug discovery. Here, we focus on 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase from the MEP pathway. We use biochemical and structural biology methods to investigate homologs from pathogenic microorganisms; Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. We determined the X-ray crystal structures of IspE-inhibitor complexes and studied inhibitors’ binding modes targeting the substrate pocket. The experimental results indicate the need for distinct inhibitor strategies due to structural differences among IspE homologs, particularly for A. baumannii IspE, which displays a unique inhibitory profile due to a tighter hydrophobic subpocket in the substrate binding site. This study enhances our understanding of the MEP enzymes and sets the stage for structure-based drug design of selective inhibitors to combat pathogenic microorganisms.
{"title":"IspE kinase as an anti-infective target: Role of a hydrophobic pocket in inhibitor binding","authors":"Rawia Hamid, Danica J. Walsh, Eleonora Diamanti, Diana Aguilar, Antoine Lacour, Mostafa M. Hamed, Anna K.H. Hirsch","doi":"10.1016/j.str.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.009","url":null,"abstract":"Enzymes of the methylerythritol phosphate (MEP) pathway are potential targets for antimicrobial drug discovery. Here, we focus on 4-diphosphocytidyl-2-<em>C</em>-methyl-D-erythritol (IspE) kinase from the MEP pathway. We use biochemical and structural biology methods to investigate homologs from pathogenic microorganisms; <em>Escherichia coli</em>, <em>Klebsiella pneumoniae</em>, and <em>Acinetobacter baumannii</em>. We determined the X-ray crystal structures of IspE-inhibitor complexes and studied inhibitors’ binding modes targeting the substrate pocket. The experimental results indicate the need for distinct inhibitor strategies due to structural differences among IspE homologs, particularly for <em>A. baumannii</em> IspE, which displays a unique inhibitory profile due to a tighter hydrophobic subpocket in the substrate binding site. This study enhances our understanding of the MEP enzymes and sets the stage for structure-based drug design of selective inhibitors to combat pathogenic microorganisms.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"25 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589076","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}
The CNNM/CorC Mg2+ transporters are widely conserved in eukaryotes (cyclin M [CNNM]) and prokaryotes (CorC) and participate in various biological processes. Previous structural analyses of the CorC transmembrane domain in the Mg2+-bound inward-facing conformation revealed the conserved Mg2+ recognition mechanism in the CNNM/CorC family; however, the conformational dynamics in the Mg2+ transport cycle remain unclear because structures in other conformations are unknown. Here, we used AlphaFold structure prediction to predict the occluded-like and outward-facing-like conformations of the CorC and CNNM proteins and identified conserved hydrophilic interactions close to the cytoplasmic side in these conformations. Molecular dynamics simulations and biochemical cross-linking showed that these conserved hydrophilic interactions are stable, especially in the outward-facing-like conformation. Furthermore, mutational analysis revealed that the residues involved in these hydrophilic interactions on the cytoplasmic side are important for Mg2+ transport in the CorC and CNNM proteins. Our work provides mechanistic insights into the transport cycle of the CNNM/CorC family.
CNNM/CorC Mg2+ 转运体在真核生物（细胞周期蛋白 M [CNNM]）和原核生物（CorC）中广泛保守，参与各种生物过程。之前对处于 Mg2+ 结合内向构象的 CorC 跨膜结构域进行的结构分析揭示了 CNNM/CorC 家族中保守的 Mg2+ 识别机制；然而，由于其他构象的结构未知，Mg2+ 转运循环中的构象动态仍不清楚。在此，我们利用 AlphaFold 结构预测法预测了 CorC 和 CNNM 蛋白的闭锁样构象和外向样构象，并确定了这些构象中靠近细胞质侧的保守亲水相互作用。分子动力学模拟和生化交联表明，这些保守的亲水相互作用是稳定的，尤其是在向外型构象中。此外，突变分析表明，参与细胞质侧这些亲水相互作用的残基对 CorC 和 CNNM 蛋白的 Mg2+ 运输非常重要。我们的研究为 CNNM/CorC 家族的转运循环提供了机制上的启示。
{"title":"AI-driven mechanistic analysis of conformational dynamics in CNNM/CorC Mg2+ transporters","authors":"Jie Ma, Xingyu Song, Yosuke Funato, Xinyu Teng, Yichen Huang, Hiroaki Miki, Wenning Wang, Motoyuki Hattori","doi":"10.1016/j.str.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.021","url":null,"abstract":"The CNNM/CorC Mg<sup>2+</sup> transporters are widely conserved in eukaryotes (cyclin M [CNNM]) and prokaryotes (CorC) and participate in various biological processes. Previous structural analyses of the CorC transmembrane domain in the Mg<sup>2+</sup>-bound inward-facing conformation revealed the conserved Mg<sup>2+</sup> recognition mechanism in the CNNM/CorC family; however, the conformational dynamics in the Mg<sup>2+</sup> transport cycle remain unclear because structures in other conformations are unknown. Here, we used AlphaFold structure prediction to predict the occluded-like and outward-facing-like conformations of the CorC and CNNM proteins and identified conserved hydrophilic interactions close to the cytoplasmic side in these conformations. Molecular dynamics simulations and biochemical cross-linking showed that these conserved hydrophilic interactions are stable, especially in the outward-facing-like conformation. Furthermore, mutational analysis revealed that the residues involved in these hydrophilic interactions on the cytoplasmic side are important for Mg<sup>2+</sup> transport in the CorC and CNNM proteins. Our work provides mechanistic insights into the transport cycle of the CNNM/CorC family.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"19 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588816","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}
Pub Date : 2024-11-05DOI: 10.1016/j.str.2024.10.019
Duy Khanh Phung, Simona Pilotto, Dorota Matelska, Fabian Blombach, Nikos Pinotsis, Ladislav Hovan, Francesco Luigi Gervasio, Finn Werner
N-utilization substance A (NusA) is a regulatory factor with pleiotropic functions in gene expression in bacteria. Archaea encode two conserved small proteins, NusA1 and NusA2, with domains orthologous to the two RNA binding K Homology (KH) domains of NusA. Here, we report the crystal structures of NusA2 from Sulfolobus acidocaldarius and Saccharolobus solfataricus obtained at 3.1 Å and 1.68 Å, respectively. NusA2 comprises an N-terminal zinc finger followed by two KH-like domains lacking the GXXG signature. Despite the loss of the GXXG motif, NusA2 binds single-stranded RNA. Mutations in the zinc finger domain compromise the structural integrity of NusA2 at high temperatures and molecular dynamics simulations indicate that zinc binding provides an energy barrier preventing the domain from reaching unfolded states. A structure-guided phylogenetic analysis of the KH-like domains supports the notion that the NusA2 clade is ancestral to the ribosomal protein eS7 in eukaryotes, implying a potential role of NusA2 in translation.
{"title":"Archaeal NusA2 is the ancestor of ribosomal protein eS7 in eukaryotes","authors":"Duy Khanh Phung, Simona Pilotto, Dorota Matelska, Fabian Blombach, Nikos Pinotsis, Ladislav Hovan, Francesco Luigi Gervasio, Finn Werner","doi":"10.1016/j.str.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.019","url":null,"abstract":"N-utilization substance A (NusA) is a regulatory factor with pleiotropic functions in gene expression in bacteria. Archaea encode two conserved small proteins, NusA1 and NusA2, with domains orthologous to the two RNA binding K Homology (KH) domains of NusA. Here, we report the crystal structures of NusA2 from <em>Sulfolobus acidocaldarius</em> and <em>Saccharolobus solfataricus</em> obtained at 3.1 Å and 1.68 Å, respectively. NusA2 comprises an N-terminal zinc finger followed by two KH-like domains lacking the GXXG signature. Despite the loss of the GXXG motif, NusA2 binds single-stranded RNA. Mutations in the zinc finger domain compromise the structural integrity of NusA2 at high temperatures and molecular dynamics simulations indicate that zinc binding provides an energy barrier preventing the domain from reaching unfolded states. A structure-guided phylogenetic analysis of the KH-like domains supports the notion that the NusA2 clade is ancestral to the ribosomal protein eS7 in eukaryotes, implying a potential role of NusA2 in translation.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"10 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580560","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}
Pub Date : 2024-11-05DOI: 10.1016/j.str.2024.10.020
Chrysa Soteriou, Mengfan Xu, Simon D. Connell, Arwen I.I. Tyler, Antreas C. Kalli, James L. Thorne
Almost four decades after the identification of the AKT protein and understanding of its role in cancer, barriers remain in the translation of AKT inhibitors for clinical applications. Here, we provide new molecular insight into the first step of AKT activation where AKT binds to the plasma membrane and its orientation is stabilized in a bilayer with lateral heterogeneity (Lo-Ld phase coexistence). We have applied molecular dynamic simulations and molecular and cell biology approaches, and demonstrate that AKT recruitment to the membrane requires a second binding site in the AKT pleckstrin homology (PH) domain that acts cooperatively with the known canonical binding site. Given the precision with which we have identified the protein-lipid interactions, the study offers new directions for AKT-targeted therapy and for testing small molecules to target these specific amino acid-PIP molecular bonds.
{"title":"Two cooperative lipid binding sites within the pleckstrin homology domain are necessary for AKT binding and stabilization to the plasma membrane","authors":"Chrysa Soteriou, Mengfan Xu, Simon D. Connell, Arwen I.I. Tyler, Antreas C. Kalli, James L. Thorne","doi":"10.1016/j.str.2024.10.020","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.020","url":null,"abstract":"Almost four decades after the identification of the AKT protein and understanding of its role in cancer, barriers remain in the translation of AKT inhibitors for clinical applications. Here, we provide new molecular insight into the first step of AKT activation where AKT binds to the plasma membrane and its orientation is stabilized in a bilayer with lateral heterogeneity (L<sub>o</sub>-L<sub>d</sub> phase coexistence). We have applied molecular dynamic simulations and molecular and cell biology approaches, and demonstrate that AKT recruitment to the membrane requires a second binding site in the AKT pleckstrin homology (PH) domain that acts cooperatively with the known canonical binding site. Given the precision with which we have identified the protein-lipid interactions, the study offers new directions for AKT-targeted therapy and for testing small molecules to target these specific amino acid-PIP molecular bonds.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"129 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580515","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}
Alternative complex III (ACIII) is a multi-subunit quinol:electron acceptor oxidoreductase that couples quinol oxidation with transmembrane proton translocation in bacterial respiratory and photosynthetic electron transport chains. Four ACIII cryoelectron microscopy (cryo-EM) structures are known. However, the effects of cryo-EM versus X-ray crystallography structure determination on ACIII structure are unclear. Here, we report a 3.25 Å crystal structure of photosynthetic ACIII from Chloroflexus aurantiacus (CaACIIIp), revealing eight subunits (ActA–G and I) with four iron-sulfur clusters and six c-type hemes, a menaquinol-binding site, and two proton translocation passages. Structural comparisons with the previously reported cryo-EM structures reveal slight local conformational changes in the solvent-exposed regions of ActB, ActD, ActG, and the transmembrane (TM) helix of subunit I. The regions conferring structural flexibility possess low sequence conservation across species. However, the core functional modules containing the menaquinol-binding pocket, redox centers, and proton translocation passages remain unchanged, preserving the enzyme’s activity.
交替复合体 III（ACIII）是一种多亚基醌：电子受体氧化还原酶，在细菌呼吸和光合电子传递链中将醌氧化与跨膜质子转运结合在一起。目前已知四种 ACIII 冷冻电镜（cryo-EM）结构。然而，低温电子显微镜与 X 射线晶体学结构测定对 ACIII 结构的影响尚不清楚。在此，我们报告了来自 Chloroflexus aurantiacus 的光合作用 ACIII（CaACIIIp）的 3.25 Å 晶体结构，揭示了八个亚基（ActA-G 和 I），其中有四个铁硫簇和六个 c 型血红素、一个甲萘醌结合位点和两个质子转运通道。与之前报道的低温电子显微镜结构比较发现，ActB、ActD、ActG 的溶剂暴露区和亚基 I 的跨膜（TM）螺旋有轻微的局部构象变化。不过，包含甲萘醌结合袋、氧化还原中心和质子转运通道的核心功能模块保持不变，从而保持了酶的活性。
{"title":"Crystal structure of the alternative complex III from the phototrophic bacterium Chloroflexus aurantiacus","authors":"Wenping Wu, Han Fang, Huimin He, Jingyi Wu, Zijun Gong, Chunyang Li, Xinkai Pei, Xiaoling Xu","doi":"10.1016/j.str.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.014","url":null,"abstract":"Alternative complex III (ACIII) is a multi-subunit quinol:electron acceptor oxidoreductase that couples quinol oxidation with transmembrane proton translocation in bacterial respiratory and photosynthetic electron transport chains. Four ACIII cryoelectron microscopy (cryo-EM) structures are known. However, the effects of cryo-EM versus X-ray crystallography structure determination on ACIII structure are unclear. Here, we report a 3.25 Å crystal structure of photosynthetic ACIII from <em>Chloroflexus aurantiacus</em> (<em>Ca</em>ACIIIp), revealing eight subunits (ActA–G and I) with four iron-sulfur clusters and six <em>c</em>-type hemes, a menaquinol-binding site, and two proton translocation passages. Structural comparisons with the previously reported cryo-EM structures reveal slight local conformational changes in the solvent-exposed regions of ActB, ActD, ActG, and the transmembrane (TM) helix of subunit I. The regions conferring structural flexibility possess low sequence conservation across species. However, the core functional modules containing the menaquinol-binding pocket, redox centers, and proton translocation passages remain unchanged, preserving the enzyme’s activity.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"73 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574504","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}
Pub Date : 2024-11-04DOI: 10.1016/j.str.2024.10.016
Saskia Lesire, Rodrigo Lata, Yannick Hoogvliets, Kune Herrebosch, Paulien Van De Velde, Anouk Speleers, Frauke Christ, Siska Van Belle, Zeger Debyser
Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein involved in transcriptional regulation and chromatin remodeling. MeCP2 exists in two isoforms, MeCP2 E1 and E2, which share the same functional domains. Loss-of-function mutations in the MeCP2 gene are the main cause of Rett syndrome (RTT). Previous studies identified a complex formation between MeCP2 and lens epithelium derived growth factor (LEDGF), a transcriptional regulator that exists in two isoforms, LEDGF/p75 and LEDGF/p52. Here, we characterized the molecular and functional interaction between MeCP2 and LEDGF. The NCoR interaction domain (NID) domain in MeCP2 is essential for the direct binding to the PWWP-CR1 region of LEDGF. Introduction of R306C, an RTT mutation in the NID of MeCP2, reduced the interaction with LEDGF. Our data reveal mutual inhibition of MeCP2 and LEDGF multimerization due to overlapping binding sites. Aligning with this observation, LEDGF depletion resulted in larger MeCP2 and DNA foci in NIH3T3 cells, suggesting a role for the MeCP2-LEDGF complex in chromatin organization.
{"title":"LEDGF interacts with the NID domain of MeCP2 and modulates MeCP2 condensates","authors":"Saskia Lesire, Rodrigo Lata, Yannick Hoogvliets, Kune Herrebosch, Paulien Van De Velde, Anouk Speleers, Frauke Christ, Siska Van Belle, Zeger Debyser","doi":"10.1016/j.str.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.016","url":null,"abstract":"Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein involved in transcriptional regulation and chromatin remodeling. MeCP2 exists in two isoforms, MeCP2 E1 and E2, which share the same functional domains. Loss-of-function mutations in the MeCP2 gene are the main cause of Rett syndrome (RTT). Previous studies identified a complex formation between MeCP2 and lens epithelium derived growth factor (LEDGF), a transcriptional regulator that exists in two isoforms, LEDGF/p75 and LEDGF/p52. Here, we characterized the molecular and functional interaction between MeCP2 and LEDGF. The NCoR interaction domain (NID) domain in MeCP2 is essential for the direct binding to the PWWP-CR1 region of LEDGF. Introduction of R306C, an RTT mutation in the NID of MeCP2, reduced the interaction with LEDGF. Our data reveal mutual inhibition of MeCP2 and LEDGF multimerization due to overlapping binding sites. Aligning with this observation, LEDGF depletion resulted in larger MeCP2 and DNA foci in NIH3T3 cells, suggesting a role for the MeCP2-LEDGF complex in chromatin organization.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"87 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574503","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}
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