Nature chemical biology最新文献_第4页

Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2–RAD51 MSANTD4和BRCA1/2-RAD51对停滞分叉处新生DNA的协同保护作用

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-14 DOI: 10.1038/s41589-024-01833-9

Haihua Xie, Lizhi Song, Genxiang Mao, Jinhua Han, Jiali Pu, Zhibing Wu, Jun Chen, Jianwei Zhou, Jun Huang, Dong Fang, Ting Liu

{"title":"Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2–RAD51","authors":"Haihua Xie, Lizhi Song, Genxiang Mao, Jinhua Han, Jiali Pu, Zhibing Wu, Jun Chen, Jianwei Zhou, Jun Huang, Dong Fang, Ting Liu","doi":"10.1038/s41589-024-01833-9","DOIUrl":"https://doi.org/10.1038/s41589-024-01833-9","url":null,"abstract":"The regressed arms of reversed replication forks exhibit structural similarities to one-ended double-stranded breaks and need to be protected against uncontrolled nucleolytic degradation. Here, we identify MSANTD4 (Myb/SANT-like DNA-binding domain-containing protein 4), a functionally uncharacterized protein that uniquely counters the replication protein A (RPA)–Bloom (BLM)/Werner syndrome helicase (WRN)–DNA replication helicase/nuclease 2 (DNA2) complex to safeguard reversed replication forks from detrimental degradation, independently of the breast cancer susceptibility proteins (BRCA1/2)–DNA repair protein RAD51 pathway. MSANTD4 specifically interacts with the junctions between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in DNA substrates harboring a 3′ overhang, which resemble the structural features of regressed arms processed by WRN–DNA2. This DNA-binding capability allows MSANTD4 to accumulate at reversed forks, strategically antagonizing the RPA–BLM/WRN–DNA2 complex by impeding its access to the ssDNA–dsDNA junction of the regressed arms. Loss of MSANTD4 exacerbates genome instability induced by replication stress in BRCA1/2-deficient cells. Our findings unveil a collaborative defense mechanism orchestrated by MSANTD4 and BRCA1/2–RAD51, effectively counteracting nucleolytic attacks on the regressed arms and synergistically preserving the integrity of reversed forks.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"26 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection 通过连续选择快速发现环肽蛋白聚集抑制剂

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-13 DOI: 10.1038/s41589-024-01823-x

Linwei Yang, Jingwei Zhang, James S. Andon, Lingjun Li, Tina Wang

引用次数: 0

Transforming an ATP-dependent enzyme into a dissipative, self-assembling system 将依赖atp的酶转化为耗散的自组装系统

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-13 DOI: 10.1038/s41589-024-01811-1

Yiying Li, Jie Zhu, Zhiyin Zhang, Jiapeng Wei, Fengbin Wang, Georg Meisl, Tuomas P. J. Knowles, Edward H. Egelman, F. Akif Tezcan

{"title":"Transforming an ATP-dependent enzyme into a dissipative, self-assembling system","authors":"Yiying Li, Jie Zhu, Zhiyin Zhang, Jiapeng Wei, Fengbin Wang, Georg Meisl, Tuomas P. J. Knowles, Edward H. Egelman, F. Akif Tezcan","doi":"10.1038/s41589-024-01811-1","DOIUrl":"https://doi.org/10.1038/s41589-024-01811-1","url":null,"abstract":"Nucleoside triphosphate (NTP)-dependent protein assemblies such as microtubules and actin filaments have inspired the development of diverse chemically fueled molecular machines and active materials but their functional sophistication has yet to be matched by design. Given this challenge, we asked whether it is possible to transform a natural adenosine 5′-triphosphate (ATP)-dependent enzyme into a dissipative self-assembling system, thereby altering the structural and functional mode in which chemical energy is used. Here we report that FtsH (filamentous temperature-sensitive protease H), a hexameric ATPase involved in membrane protein degradation, can be readily engineered to form one-dimensional helical nanotubes. FtsH nanotubes require constant energy input to maintain their integrity and degrade over time with the concomitant hydrolysis of ATP, analogous to natural NTP-dependent cytoskeletal assemblies. Yet, in contrast to natural dissipative systems, ATP hydrolysis is catalyzed by free FtsH protomers and FtsH nanotubes serve to conserve ATP, leading to transient assemblies whose lifetimes can be tuned from days to minutes through the inclusion of external ATPases in solution.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"50 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

A cell-free biosensor signal amplification circuit with polymerase strand recycling 具有聚合酶链循环的无细胞生物传感器信号放大电路

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-13 DOI: 10.1038/s41589-024-01816-w

Yueyi Li, Tyler Lucci, Matias Villarruel Dujovne, Jaeyoung Kirsten Jung, Daiana A. Capdevila, Julius B. Lucks

{"title":"A cell-free biosensor signal amplification circuit with polymerase strand recycling","authors":"Yueyi Li, Tyler Lucci, Matias Villarruel Dujovne, Jaeyoung Kirsten Jung, Daiana A. Capdevila, Julius B. Lucks","doi":"10.1038/s41589-024-01816-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01816-w","url":null,"abstract":"Cell-free systems are powerful synthetic biology technologies that can recapitulate gene expression and sensing without the complications of living cells. Cell-free systems can perform more advanced functions when genetic circuits are incorporated. Here we expand cell-free biosensing by engineering a highly specific isothermal amplification circuit called polymerase strand recycling (PSR), which leverages T7 RNA polymerase off-target transcription to recycle nucleic acid inputs within DNA strand displacement circuits. We first construct simple PSR circuits to detect different RNA targets with high specificity. We then interface PSR circuits to amplify signals from allosteric transcription factor-based biosensors for small molecule detection. A double equilibrium model of transcription factor–DNA/ligand binding predicts that PSR can improve biosensor sensitivity, which we confirm experimentally by improving the limits of detection by 10-fold to submicromolar levels for two biosensors. We believe this work expands the capabilities of cell-free circuits and demonstrates PSR’s potential for diverse applications in biotechnology.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"41 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 mechanism of temperature-dependent phase separation of heat shock factor 1 热冲击因子温度依赖性相分离的分子机理

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-10 DOI: 10.1038/s41589-024-01806-y

Qiunan Ren, Linge Li, Lei Liu, Juan Li, Chaowei Shi, Yujie Sun, Xuebiao Yao, Zhonghuai Hou, ShengQi Xiang

{"title":"The molecular mechanism of temperature-dependent phase separation of heat shock factor 1","authors":"Qiunan Ren, Linge Li, Lei Liu, Juan Li, Chaowei Shi, Yujie Sun, Xuebiao Yao, Zhonghuai Hou, ShengQi Xiang","doi":"10.1038/s41589-024-01806-y","DOIUrl":"https://doi.org/10.1038/s41589-024-01806-y","url":null,"abstract":"Heat shock factor 1 (HSF1) is the critical orchestrator of cell responses to heat shock, and its dysfunction is linked to various diseases. HSF1 undergoes phase separation upon heat shock, and its activity is regulated by post-translational modifications (PTMs). The molecular details underlying HSF1 phase separation, temperature sensing and PTM regulation remain poorly understood. Here, we discovered that HSF1 exhibits temperature-dependent phase separation with a lower critical solution temperature behavior, providing a new conceptual mechanism accounting for HSF1 activation. We revealed the residue-level molecular details of the interactions driving the phase separation of wild-type HSF1 and its distinct PTM patterns at various temperatures. The mapped interfaces were validated experimentally and accounted for the reported HSF1 functions. Importantly, the molecular grammar of temperature-dependent HSF1 phase separation is species specific and physiologically relevant. These findings delineate a chemical code that integrates accurate phase separation with physiological body temperature control in animals.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"6 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Chemically engineered antibodies for autophagy-based receptor degradation 基于自噬受体降解的化学工程抗体

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-09 DOI: 10.1038/s41589-024-01803-1

Binghua Cheng, Meiqing Li, Jiwei Zheng, Jiaming Liang, Yanyan Li, Ruijing Liang, Hui Tian, Zeyu Zhou, Li Ding, Jian Ren, Wenli Shi, Wenjie Zhou, Hailiang Hu, Long Meng, Ke Liu, Lintao Cai, Ximing Shao, Lijing Fang, Hongchang Li

{"title":"Chemically engineered antibodies for autophagy-based receptor degradation","authors":"Binghua Cheng, Meiqing Li, Jiwei Zheng, Jiaming Liang, Yanyan Li, Ruijing Liang, Hui Tian, Zeyu Zhou, Li Ding, Jian Ren, Wenli Shi, Wenjie Zhou, Hailiang Hu, Long Meng, Ke Liu, Lintao Cai, Ximing Shao, Lijing Fang, Hongchang Li","doi":"10.1038/s41589-024-01803-1","DOIUrl":"https://doi.org/10.1038/s41589-024-01803-1","url":null,"abstract":"Cell surface receptor-targeted protein degraders hold promise for drug discovery. However, their application is restricted because of the complexity of creating bifunctional degraders and the reliance on specific lysosome-shuttling receptors or E3 ubiquitin ligases. To address these limitations, we developed an autophagy-based plasma membrane protein degradation platform, which we term AUTABs (autophagy-inducing antibodies). Through covalent conjugation with polyethylenimine (PEI), the engineered antibodies acquire the capacity to degrade target receptors through autophagy. The degradation activities of AUTABs are self-sufficient, without necessitating the participation of lysosome-shuttling receptors or E3 ubiquitin ligases. The broad applicability of this platform was then illustrated by targeting various clinically important receptors. Notably, combining specific primary antibodies with a PEI-tagged secondary nanobody also demonstrated effective degradation of target receptors. Thus, our study outlines a strategy for directing plasma membrane proteins for autophagic degradation, which possesses desirable attributes such as ease of generation, independence from cell type and broad applicability.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"31 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Abiotic catalysis promoted by liquid–liquid phase separation 液-液相分离促进非生物催化

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-09 DOI: 10.1038/s41589-024-01829-5

引用次数: 0

Structure and catalytic activity of the SAM-utilizing ribozyme SAMURI 利用sam的核酶SAMURI的结构和催化活性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-08 DOI: 10.1038/s41589-024-01808-w

Hsuan-Ai Chen, Takumi Okuda, Ann-Kathrin Lenz, Carolin P. M. Scheitl, Hermann Schindelin, Claudia Höbartner

{"title":"Structure and catalytic activity of the SAM-utilizing ribozyme SAMURI","authors":"Hsuan-Ai Chen, Takumi Okuda, Ann-Kathrin Lenz, Carolin P. M. Scheitl, Hermann Schindelin, Claudia Höbartner","doi":"10.1038/s41589-024-01808-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01808-w","url":null,"abstract":"Ribozymes that catalyze site-specific RNA modification have recently gained increasing interest for their ability to mimic methyltransferase enzymes and for their application to install molecular tags. Recently, we reported SAMURI as a site-specific alkyltransferase ribozyme using S-adenosylmethionine (SAM) or a stabilized analog to transfer a methyl or propargyl group to N3 of an adenosine. Here, we report the crystal structures of SAMURI in the postcatalytic state. The structures reveal a three-helix junction with the catalytic core folded into four stacked layers, harboring the cofactor and the modified nucleotide. Detailed structure–activity analyses explain the cofactor scope and the structural basis for site selectivity. A structural comparison of SAMURI with SAM riboswitches sheds light on how the synthetic ribozyme overcomes the strategies of natural riboswitches to avoid self-methylation. Our results suggest that SAM and its analogs may serve as substrates for various RNA-catalyzed reactions, for which the corresponding ribozymes remain to be identified.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"30 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Population-level amplification of gene regulation by programmable gene transfer 可编程基因转移在群体水平上的基因调控扩增

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-08 DOI: 10.1038/s41589-024-01817-9

Hye-In Son, Grayson S. Hamrick, Ashwini R. Shende, Kyeri Kim, Kaichun Yang, Tony Jun Huang, Lingchong You

引用次数: 0

Artificial metalloenzyme assembly in cellular compartments for enhanced catalysis 用于增强催化作用的细胞室人工金属酶组装

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-08 DOI: 10.1038/s41589-024-01819-7

Tong Wu, Xianhui Chen, Yating Fei, Guopu Huang, Yingjiao Deng, Yingjie Wang, Anming Yang, Zhiyong Chen, N. Gabriel Lemcoff, Xinxin Feng, Yugang Bai

{"title":"Artificial metalloenzyme assembly in cellular compartments for enhanced catalysis","authors":"Tong Wu, Xianhui Chen, Yating Fei, Guopu Huang, Yingjiao Deng, Yingjie Wang, Anming Yang, Zhiyong Chen, N. Gabriel Lemcoff, Xinxin Feng, Yugang Bai","doi":"10.1038/s41589-024-01819-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01819-7","url":null,"abstract":"Artificial metalloenzymes (ArMs) integrated within whole cells have emerged as promising catalysts; however, their sensitivity to metal centers remains a systematic challenge, resulting in diminished activity and turnover. Here we address this issue by inducing in cellulo liquid–liquid phase separation through a self-labeling fusion protein, HaloTag–SNAPTag. This strategy creates membraneless, isolated liquid condensates within Escherichia coli as protective compartments for the assembly of ArMs using the same fusion protein. The approach allows for high ArM loading and stabilization by localizing the ArMs within the phase-separated regions. Consequently, the performance of ArM-based whole-cell catalysts is improved, with a demonstrated turnover per cell of up to 7.1 × 109 for the olefin metathesis reaction. Furthermore, we apply this to an engineered E. coli system in live mice, where host bacterial cells confine the metal catalytic species, and in a mouse colorectal cancer model, where ArM-containing whole-cell catalysts mediate concurrent reactions to activate prodrugs.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"36 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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