Nature structural & molecular biology最新文献_第3页

Structural clues about bridge-mediated lipid transfer 桥介导的脂质转移的结构线索

Nature structural & molecular biology Pub Date : 2025-05-15 DOI: 10.1038/s41594-025-01552-2

Pietro De Camilli, Karin M. Reinisch

引用次数: 0

Insights into the degradation mechanism of GID4-based proteolysis-targeting chimeras 基于gid4蛋白水解靶向嵌合体降解机制的研究

Nature structural & molecular biology Pub Date : 2025-05-15 DOI: 10.1038/s41594-025-01539-z

引用次数: 0

Reciprocal stabilization of CtBP and TRIM28 represses autophagy to promote metastasis CtBP和TRIM28的相互稳定抑制自噬，促进转移

Nature structural & molecular biology Pub Date : 2025-05-15 DOI: 10.1038/s41594-025-01554-0

Lixin Tai, Dongliang Zhu, Ping Tang, Jiajia Li, Junyi Li, Peipei Li, Zhonghua Tao, Haipeng Lei, Kai Miao, Hong-xia Wang, Shuhai Lin, Lei Zhang, Man Dou, Yu Han, Han-Ming Shen, Chuxia Deng, Li Wang, Li-jun Di

{"title":"Reciprocal stabilization of CtBP and TRIM28 represses autophagy to promote metastasis","authors":"Lixin Tai, Dongliang Zhu, Ping Tang, Jiajia Li, Junyi Li, Peipei Li, Zhonghua Tao, Haipeng Lei, Kai Miao, Hong-xia Wang, Shuhai Lin, Lei Zhang, Man Dou, Yu Han, Han-Ming Shen, Chuxia Deng, Li Wang, Li-jun Di","doi":"10.1038/s41594-025-01554-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01554-0","url":null,"abstract":"Deciphering the processes through which cancer cells overcome stress, escape a repressive microenvironment and metastasize remains a challenge. Autophagy has been demonstrated to regulate cancer metastasis and C-terminal binding protein (CtBP) has been previously implicated in promoting metastasis in breast cancer. Here we identify the formation of a complex between CtBP and tripartite-motif-containing protein 28 (TRIM28) in the nucleus. Interestingly, this complex regulates the stability of both proteins, as the removal of either partner leads to degradation of the other. Furthermore, the stability of this complex in the nucleus inhibits autophagy through two independent mechanisms. Firstly, the formation of the complex sequesters TRIM28 in the nucleus, preventing its involvement in and its degradation through autophagy. Secondly, this complex participates in the suppression of PTEN expression and leads to inhibition of Unc-51-like kinase 1-mediated autophagy through activation of the protein kinase B–mammalian target of rapamycin pathway. Using mammary gland-specific CtBP-knockout mice, we demonstrate that repression of autophagy by the CtBP–TRIM28 complex modulates luminal duct formation. In breast cancer models, CtBP–TRIM28-dependent inhibition of cellular autophagy also promotes malignant metastasis. Therefore, our study reveals similarities between the mechanisms driving tumor progression and those involved in normal mammary gland development, potentially helping to pave the way toward targeted intervention in breast cancer metastasis.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979577","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

STING to the lysosome’s rescue STING对溶酶体的拯救

Nature structural & molecular biology Pub Date : 2025-05-13 DOI: 10.1038/s41594-025-01563-z

Katarzyna A. Ciazynska

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Visualizing RNA oligomers 可视化RNA低聚物

Nature structural & molecular biology Pub Date : 2025-05-13 DOI: 10.1038/s41594-025-01569-7

Katarzyna Marcinkiewicz

{"title":"Visualizing RNA oligomers","authors":"Katarzyna Marcinkiewicz","doi":"10.1038/s41594-025-01569-7","DOIUrl":"https://doi.org/10.1038/s41594-025-01569-7","url":null,"abstract":"The stability and function of many biological macromolecules are regulated by assembling several identical subunits into larger structures. So far, this phenomenon has been best studied in proteins. Now, in a study in Science, Wang et al. use single-particle cryo-electron microscopy (cryo-EM) to visualize several quaternary structures of RNA. The group selected four bacterial noncoding RNA families anticipated to adopt higher-level structures and with known or predicted functions: ARRPOF, OLE, ROOL and GOLLD.The RNA for cryo-EM structure determination was synthesized by in vitro transcription, purified and allowed to refold before imaging. The reconstructions of ARRPOF and OLE revealed homodimers, whereas ROOL and GOLLD formed cage-like particles — a tetramer and hexamers, octamers, decamers or dodecamers. The types of interaction between the protomers within these larger assemblies included intermolecular complementary base-pairings, pseudoknots, sheared A-A pairings, continuous A-stacking, kissing-loop, tetraloop/tetraloop receptor (TL/TLR), loop-bulge and minor-groove interactions — a variety that reflects RNA versatility and the basis of its multivalency. Many of the sequences that underlie these interactions are conserved, which suggests that the resulting quaternary architecture is crucial for the function of these RNAs within the cell. However, an attempt to use a pre-trained contrastive learning language model to further analyze the revealed relationships between RNA sequences and structures yielded limited success, likely due to the insufficient numbers of RNA structures available to train computational models.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940150","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

CTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation CTCF耗竭使增强子介导的基因活化与染色质中心形成脱钩

Nature structural & molecular biology Pub Date : 2025-05-13 DOI: 10.1038/s41594-025-01555-z

Magdalena A. Karpinska, Yi Zhu, Zahra Fakhraei Ghazvini, Shyam Ramasamy, Mariano Barbieri, T. B. Ngoc Cao, Natalie Varahram, Abrar Aljahani, Michael Lidschreiber, Argyris Papantonis, A. Marieke Oudelaar

{"title":"CTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation","authors":"Magdalena A. Karpinska, Yi Zhu, Zahra Fakhraei Ghazvini, Shyam Ramasamy, Mariano Barbieri, T. B. Ngoc Cao, Natalie Varahram, Abrar Aljahani, Michael Lidschreiber, Argyris Papantonis, A. Marieke Oudelaar","doi":"10.1038/s41594-025-01555-z","DOIUrl":"https://doi.org/10.1038/s41594-025-01555-z","url":null,"abstract":"Enhancers and promoters interact in three-dimensional (3D) chromatin structures to regulate gene expression. Here we characterize the mechanisms that drive the formation and function of these structures in a lymphoid-to-myeloid transdifferentiation system. Based on analyses at base pair resolution, we demonstrate a close correlation between binding of regulatory proteins, formation of chromatin interactions and gene expression. Multi-way interaction analyses and computational modeling show that tissue-specific gene loci are organized into chromatin hubs, characterized by cooperative interactions between multiple enhancers, promoters and CTCF-binding sites. While depletion of CTCF strongly impairs the formation of these chromatin hubs, the effects of CTCF depletion on gene expression are modest and can be explained by rewired enhancer–promoter interactions. These findings demonstrate a role for enhancer–promoter interactions in gene regulation that is independent of cooperative interactions in chromatin hubs. Together, these results contribute to our understanding of the structure–function relationship of the genome during cellular differentiation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"142 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940145","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

Decoupling chromatin hubs from gene control 从基因控制中分离染色质中心

Nature structural & molecular biology Pub Date : 2025-05-13 DOI: 10.1038/s41594-025-01544-2

Darío G. Lupiáñez

引用次数: 0

Flexing protein assemblies 弯曲蛋白组合

Nature structural & molecular biology Pub Date : 2025-05-12 DOI: 10.1038/s41594-025-01560-2

Yang Li, Yang Zhang

引用次数: 0

Slow awakening of the silent X chromosome in female primordial germ cells 雌性原始生殖细胞中沉默的X染色体的缓慢觉醒

Nature structural & molecular biology Pub Date : 2025-05-05 DOI: 10.1038/s41594-025-01550-4

Christine M. Disteche, Xinxian Deng

引用次数: 0

Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30 嵌合去泛素酶工程揭示了特异性抑制线粒体自噬调节因子USP30的结构基础

Nature structural & molecular biology Pub Date : 2025-05-05 DOI: 10.1038/s41594-025-01534-4

Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch

{"title":"Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30","authors":"Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch","doi":"10.1038/s41594-025-01534-4","DOIUrl":"https://doi.org/10.1038/s41594-025-01534-4","url":null,"abstract":"The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1–parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson’s disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910288","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