Nature structural & molecular biology最新文献_第4页

Cytoplasmic PXR regulates glucose metabolism by binding mRNAs and modulating their stability 胞质PXR通过结合mrna并调节其稳定性来调节葡萄糖代谢

Nature structural & molecular biology Pub Date : 2025-08-12 DOI: 10.1038/s41594-025-01614-5

Xiaofei Wang, Zehua Wang, Sihan Li, Dhamotharan Pattarayan, Yifei Wang, Jingchen Zhai, Yu Zhang, Haolin Wang, Meishu Xu, Junjie Zhu, Junmei Wang, Xiaochao Ma, Sridhar Mani, Wen Xie, Min Zhang, Da Yang

{"title":"Cytoplasmic PXR regulates glucose metabolism by binding mRNAs and modulating their stability","authors":"Xiaofei Wang, Zehua Wang, Sihan Li, Dhamotharan Pattarayan, Yifei Wang, Jingchen Zhai, Yu Zhang, Haolin Wang, Meishu Xu, Junjie Zhu, Junmei Wang, Xiaochao Ma, Sridhar Mani, Wen Xie, Min Zhang, Da Yang","doi":"10.1038/s41594-025-01614-5","DOIUrl":"https://doi.org/10.1038/s41594-025-01614-5","url":null,"abstract":"Pregnane X receptor (PXR) is a nuclear receptor considered to be a master transcription factor of xenobiotic metabolism. Here, using enhanced ultraviolet crosslinking and immunoprecipitation, we show that PXR can bind mRNAs in different cancer cell lines and normal liver tissues. PXR-bound mRNAs include genes related to metabolic reprogramming and lipid metabolism. Separately from its known nuclear transcriptional function, cytoplasmic PXR binds and stabilizes mature mRNA containing C+G-enriched sequences through its zinc-finger domain. Mechanistically, cytoplasmic PXR interacts with RNH1, an RNase inhibitor, to regulate RNA stability. In colorectal cancer cells, cytoplasmic PXR facilitates glucose uptake by stabilizing SLC2A1 mRNA. This process further promotes cell proliferation and cancer development. Our study unveils a previously unknown dimension of PXR-mediated gene regulation by characterizing PXR as an RNA-binding protein important for mRNA stability in the cytoplasm.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural analyses define the molecular basis of clusterin chaperone function 结构分析确定了簇蛋白伴侣功能的分子基础

Nature structural & molecular biology Pub Date : 2025-08-08 DOI: 10.1038/s41594-025-01631-4

Patricia Yuste-Checa, Alonso I. Carvajal, Chenchen Mi, Sarah Paatz, F. Ulrich Hartl, Andreas Bracher

{"title":"Structural analyses define the molecular basis of clusterin chaperone function","authors":"Patricia Yuste-Checa, Alonso I. Carvajal, Chenchen Mi, Sarah Paatz, F. Ulrich Hartl, Andreas Bracher","doi":"10.1038/s41594-025-01631-4","DOIUrl":"https://doi.org/10.1038/s41594-025-01631-4","url":null,"abstract":"Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two disordered, hydrophobic peptide tails enable diverse activities. Resembling the substrate-binding regions of small heat-shock proteins, these sequences mediate clusterin’s chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with conserved surface areas, the tail segments also participate in clusterin binding to cell surface receptors and cellular uptake. While contributing to lipoprotein formation, the hydrophobic tails remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipids in maintaining the solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"165 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Establishment of the phagophore–ERES membrane contact site initiates phagophore elongation 噬菌体- eres膜接触位点的建立启动了噬菌体延伸

Nature structural & molecular biology Pub Date : 2025-08-07 DOI: 10.1038/s41594-025-01621-6

Rubén Gómez-Sánchez, Sabrina Chumpen Ramirez, Prado Vargas Duarte, Yan Hu, Muriel Mari, Katharina Olschewski, Ralph Hardenberg, J. Christopher Fromme, Christian Ungermann, Fulvio Reggiori

{"title":"Establishment of the phagophore–ERES membrane contact site initiates phagophore elongation","authors":"Rubén Gómez-Sánchez, Sabrina Chumpen Ramirez, Prado Vargas Duarte, Yan Hu, Muriel Mari, Katharina Olschewski, Ralph Hardenberg, J. Christopher Fromme, Christian Ungermann, Fulvio Reggiori","doi":"10.1038/s41594-025-01621-6","DOIUrl":"https://doi.org/10.1038/s41594-025-01621-6","url":null,"abstract":"The de novo generation of membrane contact sites (MCSs) between the phagophore and the endoplasmic reticulum exit sites (ERES) is important for the acquisition of the lipids necessary for phagophore elongation and autophagosome formation during autophagy. However, it is currently unclear how these MCSs are established. Here, we show that the TRAPPIII complex, the guanine nucleotide exchange factor of the Rab GTPase Ypt1, localizes to and regulates the formation of the MCS between the phagophore and the ERES. In particular, TRAPPIII and the lipid transfer protein Atg2 appear equally essential for the association of the phagophore with the ERES, TRAPPIII activation and Ypt1 activation onto the phagophore. Ypt1 redistributes over the entire surface of the phagophore and promotes its elongation through both stimulation of the local biosynthesis of phosphatidylinositol-3-phosphate and recruitment of the downstream effectors Atg18 and Atg21. Our data suggest that de novo generation of the phagophore–ER MCSs and subsequent Ypt1 activation initiates phagophore elongation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Building bridges for autophagy 为自噬搭建桥梁

Nature structural & molecular biology Pub Date : 2025-08-07 DOI: 10.1038/s41594-025-01628-z

Anne Schreiber

引用次数: 0

Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4 核心剪接结构和早期剪接体识别决定了微外显子对SRRM3/4的敏感性

Nature structural & molecular biology Pub Date : 2025-08-07 DOI: 10.1038/s41594-025-01634-1

Sophie Bonnal, Simon Bajew, Rosa Martinez-Corral, Manuel Irimia

引用次数: 0

Returning home: there and back again in Czechia 回家：在那里，又回到捷克

Nature structural & molecular biology Pub Date : 2025-08-07 DOI: 10.1038/s41594-025-01642-1

Hana Polasek-Sedlackova

引用次数: 0

Structural insights into higher-order natural RNA-only multimers 对高阶天然rna多聚体的结构见解

Nature structural & molecular biology Pub Date : 2025-08-06 DOI: 10.1038/s41594-025-01650-1

Shengchun Zhang, Ran Yi, Linfeng An, Ji Liu, Xuebiao Yao, Shanshan Li, Kaiming Zhang

{"title":"Structural insights into higher-order natural RNA-only multimers","authors":"Shengchun Zhang, Ran Yi, Linfeng An, Ji Liu, Xuebiao Yao, Shanshan Li, Kaiming Zhang","doi":"10.1038/s41594-025-01650-1","DOIUrl":"https://doi.org/10.1038/s41594-025-01650-1","url":null,"abstract":"RNA-only complexes adopt intricate three-dimensional structures to fulfill diverse functions independently of protein partners. Although multimeric RNA-only structures have been engineered in synthetic RNA nanomaterials, naturally occurring RNA-only complexes have primarily been observed as monomers or dimers, leaving higher-order assemblies largely unexplored. ROOL (rumen-originating, ornate, large) and GOLLD (giant, ornate, lake- and Lactobacillales-derived) RNAs are conserved non-coding RNAs with complex secondary structures, but their high-resolution architectures remain unknown. Here, we determine the cryo-electron microscopy structures of UCC118-Rool RNA, Sag-Golld RNA and Env38-Golld RNA at 1.96–2.98 Å resolution, revealing their distinct hexameric, decameric and tetradecameric assemblies. These higher-order architectures are stabilized by an array of tertiary motifs such as kissing loops and tetraloop–receptor motifs, underscoring the conserved principles of RNA self-assembly. By elucidating the molecular details of these higher-order RNA-only assemblies, this study expands our understanding of RNA-based architectures and broadens the scope of RNA structural biology.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure of the TXNL1-bound proteasome txnl1结合蛋白酶体的结构

Nature structural & molecular biology Pub Date : 2025-08-06 DOI: 10.1038/s41594-025-01639-w

Jingjing Gao, Christopher Nardone, Matthew C. J. Yip, Haruka Chino, Xin Gu, Zachary Mirman, Michael J. Rale, Joao A. Paulo, Stephen J. Elledge, Sichen Shao

引用次数: 0

GAGA zinc finger transcription factor searches chromatin by 1D–3D facilitated diffusion GAGA锌指转录因子通过1D-3D扩散寻找染色质

Nature structural & molecular biology Pub Date : 2025-08-05 DOI: 10.1038/s41594-025-01643-0

Xinyu A. Feng, Maryam Yamadi, Yiben Fu, Kaitlin M. Ness, Celina Liu, Ishtiyaq Ahmed, Gregory D. Bowman, Margaret E. Johnson, Taekjip Ha, Carl Wu

{"title":"GAGA zinc finger transcription factor searches chromatin by 1D–3D facilitated diffusion","authors":"Xinyu A. Feng, Maryam Yamadi, Yiben Fu, Kaitlin M. Ness, Celina Liu, Ishtiyaq Ahmed, Gregory D. Bowman, Margaret E. Johnson, Taekjip Ha, Carl Wu","doi":"10.1038/s41594-025-01643-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01643-0","url":null,"abstract":"The search for target sites on chromatin by eukaryotic sequence-specific transcription factors (TFs) is integral to the regulation of gene expression but the mechanism of nuclear exploration has remained obscure. Here we use multicolor single-molecule fluorescence resonance energy transfer and single-particle imaging to track the diffusion of purified Drosophila GAGA factor (GAF) on DNA and nucleosomes. Monomeric GAF DNA-binding domain (DBD) bearing one zinc finger finds its cognate site through one-dimensional (1D) or three-dimensional (3D) diffusion on bare DNA and rapidly slides back and forth between naturally clustered motifs for seconds before dissociation. Multimeric, full-length GAF also finds clustered motifs on DNA through 1D–3D diffusion but remains locked on target for longer periods. Nucleosome architecture effectively blocks GAF-DBD 1D sliding into the histone core but favors retention of GAF-DBD once it has bound to a solvent-exposed motif through 3D diffusion. Despite the occlusive nature of nucleosomes, 1D–3D facilitated diffusion enables GAF to effectively search for clustered cognate motifs in chromatin, providing a mechanism for navigation to nucleosomal and nucleosome-free sites by a member of the zinc finger TF family.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 lamin-specific chromatin interactions 核纤层蛋白特异性染色质相互作用的分子基础

Nature structural & molecular biology Pub Date : 2025-08-01 DOI: 10.1038/s41594-025-01622-5

Baihui Wang, Rafael Kronenberg-Tenga, Valentina Rosti, Emanuele Di Patrizio Soldateschi, Qiang Luo, Ugo Maria Iannacchero, Louise Pinet, Matthias Eibauer, Rajaa Boujemaa-Paterski, Benjamin Schuler, Chiara Lanzuolo, Ohad Medalia

{"title":"The molecular basis of lamin-specific chromatin interactions","authors":"Baihui Wang, Rafael Kronenberg-Tenga, Valentina Rosti, Emanuele Di Patrizio Soldateschi, Qiang Luo, Ugo Maria Iannacchero, Louise Pinet, Matthias Eibauer, Rajaa Boujemaa-Paterski, Benjamin Schuler, Chiara Lanzuolo, Ohad Medalia","doi":"10.1038/s41594-025-01622-5","DOIUrl":"https://doi.org/10.1038/s41594-025-01622-5","url":null,"abstract":"In the cell nucleus, chromatin is anchored to the nuclear lamina, a network of lamin filaments and binding proteins that underly the inner nuclear membrane. The nuclear lamina is involved in chromatin organization through the interaction of lamina-associated domains within the densely packed heterochromatin regions. Using cryo-focused ion beam milling in conjunction with cryo-electron tomography, we analyzed the distribution of nucleosomes at the lamin–chromatin interface at the nanometer scale. Depletion of lamins A and C reduced nucleosome concentration at the nuclear periphery, while B-type lamin depletion contributed to nucleosome density in proximity to the lamina but not further away. We then investigated whether specific lamins can mediate direct interactions with chromatin. Using cryo-electron microscopy, we identified a specific binding motif of the lamin A tail domain that interacts with nucleosomes, distinguishing it from the other lamin isoforms. Furthermore, we examined chromatin structure dynamics using a genome-wide analysis that revealed lamin-dependent macroscopic-scale alterations in gene expression and chromatin remodeling. Our findings provide detailed insights into the dynamic and structural interplay between lamin isoforms and chromatin, molecular interactions that shape chromatin architecture and epigenetic regulation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0