Nature chemical biology最新文献_第7页

An engineered trafficking biosensor reveals a role for DNAJC13 in DOR downregulation 工程化贩运生物传感器揭示了DNAJC13在DOR下调中的作用

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-02 DOI: 10.1038/s41589-024-01705-2

Brandon Novy, Aleksandra Dagunts, Tatum Weishaar, Emily E. Holland, Hayden Adoff, Emily Hutchinson, Monica De Maria, Martin Kampmann, Nikoleta G. Tsvetanova, Braden T. Lobingier

{"title":"An engineered trafficking biosensor reveals a role for DNAJC13 in DOR downregulation","authors":"Brandon Novy, Aleksandra Dagunts, Tatum Weishaar, Emily E. Holland, Hayden Adoff, Emily Hutchinson, Monica De Maria, Martin Kampmann, Nikoleta G. Tsvetanova, Braden T. Lobingier","doi":"10.1038/s41589-024-01705-2","DOIUrl":"https://doi.org/10.1038/s41589-024-01705-2","url":null,"abstract":"Trafficking of G protein-coupled receptors (GPCRs) through the endosomal–lysosomal pathway is critical to homeostatic regulation of GPCRs following activation with agonist. Identifying the genes involved in GPCR trafficking is challenging due to the complexity of sorting operations and the large number of cellular proteins involved in the process. Here, we developed a high-sensitivity biosensor for GPCR expression and agonist-induced trafficking to the lysosome by leveraging the ability of the engineered peroxidase APEX2 to activate the fluorogenic substrate Amplex UltraRed (AUR). We used the GPCR–APEX2/AUR assay to perform a genome-wide CRISPR interference screen focused on identifying genes regulating expression and trafficking of the δ-opioid receptor (DOR). We identified 492 genes consisting of both known and new regulators of DOR function. We demonstrate that one new regulator, DNAJC13, controls trafficking of multiple GPCRs, including DOR, through the endosomal–lysosomal pathway by regulating the composition of the endosomal proteome and endosomal homeostasis.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"35 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118188","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

Engineering artificial non-coding RNAs for targeted protein degradation 工程化人工非编码 RNA，实现有针对性的蛋白质降解

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-30 DOI: 10.1038/s41589-024-01719-w

Congcong Cao, Aolin Li, Chaojie Xu, Baorui Wu, Lin Yao, Yuchen Liu

引用次数: 0

µMap proximity labeling in living cells reveals stress granule disassembly mechanisms 活细胞中的 µMap 近距离标记揭示了应力颗粒的解体机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-30 DOI: 10.1038/s41589-024-01721-2

Chenmengxiao (Roderick) Pan, Steve D. Knutson, Sean W. Huth, David W. C. MacMillan

{"title":"µMap proximity labeling in living cells reveals stress granule disassembly mechanisms","authors":"Chenmengxiao (Roderick) Pan, Steve D. Knutson, Sean W. Huth, David W. C. MacMillan","doi":"10.1038/s41589-024-01721-2","DOIUrl":"https://doi.org/10.1038/s41589-024-01721-2","url":null,"abstract":"Phase-separated condensates are membrane-less intracellular structures comprising dynamic protein interactions that organize essential biological processes. Understanding the composition and dynamics of these organelles advances our knowledge of cellular behaviors and disease pathologies related to granule dysregulation. In this study, we apply microenvironment mapping with a HaloTag-based platform (HaloMap) to characterize intracellular stress granule dynamics in living cells. After validating the robustness and sensitivity of this approach, we then profile the stress granule proteome throughout the formation and disassembly and under pharmacological perturbation. These experiments reveal several ubiquitin-related modulators, including the HECT (homologous to E6AP C terminus) E3 ligases ITCH and NEDD4L, as well as the ubiquitin receptor toll-interacting protein TOLLIP, as key mediators of granule disassembly. In addition, we identify an autophagy-related pathway that promotes granule clearance. Collectively, this work establishes a general photoproximity labeling approach for unraveling intracellular protein interactomes and uncovers previously unexplored regulatory mechanisms of stress granule dynamics.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"7 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142101699","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

Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors 用合成转录抑制因子直接抑制肿瘤缺氧反应

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-30 DOI: 10.1038/s41589-024-01716-z

Zeyu Qiao, Long C. Nguyen, Dongbo Yang, Christopher Dann, Deborah M. Thomas, Madeline Henn, Andrea Valdespino, Colin S. Swenson, Scott A. Oakes, Marsha Rich Rosner, Raymond E. Moellering

{"title":"Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors","authors":"Zeyu Qiao, Long C. Nguyen, Dongbo Yang, Christopher Dann, Deborah M. Thomas, Madeline Henn, Andrea Valdespino, Colin S. Swenson, Scott A. Oakes, Marsha Rich Rosner, Raymond E. Moellering","doi":"10.1038/s41589-024-01716-z","DOIUrl":"https://doi.org/10.1038/s41589-024-01716-z","url":null,"abstract":"Many oncogenic transcription factors (TFs) are considered to be undruggable because of their reliance on large protein–protein and protein–DNA interfaces. TFs such as hypoxia-inducible factors (HIFs) and X-box-binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to unfolded protein response element (UPRE) and hypoxia-induced response element (HRE) motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the basic leucine zipper domain of XBP1 and recognize UPRE and HRE motifs. A lead molecule, STR22, binds UPRE and HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1α binding to HRE-containing promoters and enhancers, inhibits hypoxia-induced gene expression and blocks protumorigenic phenotypes in triple-negative breast cancer (TNBC) cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF–DNA binding.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"7 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142101697","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

Genetic control over biogenic crystal morphogenesis in zebrafish 斑马鱼生物晶体形态发生的遗传控制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-30 DOI: 10.1038/s41589-024-01722-1

Rachael Deis, Tali Lerer-Goldshtein, Olha Baiko, Zohar Eyal, Dolev Brenman-Begin, Moshe Goldsmith, Sylvia Kaufmann, Uwe Heinig, Yonghui Dong, Sofya Lushchekina, Neta Varsano, Tsviya Olender, Meital Kupervaser, Ziv Porat, Smadar Levin-Zaidman, Iddo Pinkas, Rita Mateus, Dvir Gur

{"title":"Genetic control over biogenic crystal morphogenesis in zebrafish","authors":"Rachael Deis, Tali Lerer-Goldshtein, Olha Baiko, Zohar Eyal, Dolev Brenman-Begin, Moshe Goldsmith, Sylvia Kaufmann, Uwe Heinig, Yonghui Dong, Sofya Lushchekina, Neta Varsano, Tsviya Olender, Meital Kupervaser, Ziv Porat, Smadar Levin-Zaidman, Iddo Pinkas, Rita Mateus, Dvir Gur","doi":"10.1038/s41589-024-01722-1","DOIUrl":"https://doi.org/10.1038/s41589-024-01722-1","url":null,"abstract":"Organisms evolve mechanisms that regulate the properties of biogenic crystals to support a wide range of functions, from vision and camouflage to communication and thermal regulation. Yet, the mechanism underlying the formation of diverse intracellular crystals remains enigmatic. Here we unravel the biochemical control over crystal morphogenesis in zebrafish iridophores. We show that the chemical composition of the crystals determines their shape, particularly through the ratio between the nucleobases guanine and hypoxanthine. We reveal that these variations in composition are genetically controlled through tissue-specific expression of specialized paralogs, which exhibit remarkable substrate selectivity. This orchestrated combination grants the organism with the capacity to generate a broad spectrum of crystal morphologies. Overall, our findings suggest a mechanism for the morphological and functional diversity of biogenic crystals and may, thus, inspire the development of genetically designed biomaterials and medical therapeutics.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"10 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142101700","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

Coaching LSD1 to ignore acetylation 教导 LSD1 忽略乙酰化

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-28 DOI: 10.1038/s41589-024-01710-5

Joshua C. Black, Tatiana G. Kutateladze

引用次数: 0

Author Correction: Balancing G protein selectivity and efficacy in the adenosine A_2A receptor. 作者更正：平衡腺苷 A2A 受体中 G 蛋白的选择性和功效。

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-08-28 DOI: 10.1038/s41589-024-01732-z

Louis-Philippe Picard, Alexander Orazietti, Duy Phuoc Tran, Andrejs Tucs, Sari Hagimoto, Zhenzhou Qi, Shuya Kate Huang, Koji Tsuda, Akio Kitao, Adnan Sljoka, R Scott Prosser

引用次数: 0

Massively parallel measurement of protein–protein interactions by sequencing using MP3-seq 利用 MP3-seq 测序技术大规模并行测量蛋白质与蛋白质之间的相互作用。

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-08-27 DOI: 10.1038/s41589-024-01718-x

Alexandr Baryshev, Alyssa La Fleur, Benjamin Groves, Cirstyn Michel, David Baker, Ajasja Ljubetič, Georg Seelig

{"title":"Massively parallel measurement of protein–protein interactions by sequencing using MP3-seq","authors":"Alexandr Baryshev, Alyssa La Fleur, Benjamin Groves, Cirstyn Michel, David Baker, Ajasja Ljubetič, Georg Seelig","doi":"10.1038/s41589-024-01718-x","DOIUrl":"10.1038/s41589-024-01718-x","url":null,"abstract":"Protein–protein interactions (PPIs) regulate many cellular processes and engineered PPIs have cell and gene therapy applications. Here, we introduce massively parallel PPI measurement by sequencing (MP3-seq), an easy-to-use and highly scalable yeast two-hybrid approach for measuring PPIs. In MP3-seq, DNA barcodes are associated with specific protein pairs and barcode enrichment can be read by sequencing to provide a direct measure of interaction strength. We show that MP3-seq is highly quantitative and scales to over 100,000 interactions. We apply MP3-seq to characterize interactions between families of rationally designed heterodimers and to investigate elements conferring specificity to coiled-coil interactions. Lastly, we predict coiled heterodimer structures using AlphaFold-Multimer (AF-M) and train linear models on physics-based energy terms to predict MP3-seq values. We find that AF-M-based models could be valuable for prescreening interactions but experimentally measuring interactions remains necessary to rank their strengths quantitatively. A method called massively parallel PPI measurement by sequencing (MP3-seq) is developed for measuring protein–protein interactions at scale. MP3-seq uses DNA barcodes that are associated with specific protein pairs and provides a quantitative measure of interaction strength. Interactions between rationally designed heterodimers and elements conferring interaction specificity were investigated using MP3-seq.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"20 11","pages":"1514-1523"},"PeriodicalIF":12.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis for intermodular communication in assembly-line polyketide biosynthesis 组装线多酮生物合成中模块间通信的结构基础

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-23 DOI: 10.1038/s41589-024-01709-y

Dillon P. Cogan, Alexander M. Soohoo, Muyuan Chen, Yan Liu, Krystal L. Brodsky, Chaitan Khosla

{"title":"Structural basis for intermodular communication in assembly-line polyketide biosynthesis","authors":"Dillon P. Cogan, Alexander M. Soohoo, Muyuan Chen, Yan Liu, Krystal L. Brodsky, Chaitan Khosla","doi":"10.1038/s41589-024-01709-y","DOIUrl":"https://doi.org/10.1038/s41589-024-01709-y","url":null,"abstract":"Assembly-line polyketide synthases (PKSs) are modular multi-enzyme systems with considerable potential for genetic reprogramming. Understanding how they selectively transport biosynthetic intermediates along a defined sequence of active sites could be harnessed to rationally alter PKS product structures. To investigate functional interactions between PKS catalytic and substrate acyl carrier protein (ACP) domains, we employed a bifunctional reagent to crosslink transient domain–domain interfaces of a prototypical assembly line, the 6-deoxyerythronolide B synthase, and resolved their structures by single-particle cryogenic electron microscopy (cryo-EM). Together with statistical per-particle image analysis of cryo-EM data, we uncovered interactions between ketosynthase (KS) and ACP domains that discriminate between intra-modular and inter-modular communication while reinforcing the relevance of conformational asymmetry during the catalytic cycle. Our findings provide a foundation for the structure-based design of hybrid PKSs comprising biosynthetic modules from different naturally occurring assembly lines.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"11 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042594","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

Degradable living plastics programmed by engineered spores 由工程孢子编程的可降解活塑料

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-08-21 DOI: 10.1038/s41589-024-01713-2

Chenwang Tang, Lin Wang, Jing Sun, Guangda Chen, Junfeng Shen, Liang Wang, Ying Han, Jiren Luo, Zhiying Li, Pei Zhang, Simin Zeng, Dianpeng Qi, Jin Geng, Ji Liu, Zhuojun Dai

{"title":"Degradable living plastics programmed by engineered spores","authors":"Chenwang Tang, Lin Wang, Jing Sun, Guangda Chen, Junfeng Shen, Liang Wang, Ying Han, Jiren Luo, Zhiying Li, Pei Zhang, Simin Zeng, Dianpeng Qi, Jin Geng, Ji Liu, Zhuojun Dai","doi":"10.1038/s41589-024-01713-2","DOIUrl":"https://doi.org/10.1038/s41589-024-01713-2","url":null,"abstract":"Plastics are widely used materials that pose an ecological challenge because their wastes are difficult to degrade. Embedding enzymes and biomachinery within polymers could enable the biodegradation and disposal of plastics. However, enzymes rarely function under conditions suitable for polymer processing. Here, we report degradable living plastics by harnessing synthetic biology and polymer engineering. We engineered Bacillus subtilis spores harboring the gene circuit for the xylose-inducible secretory expression of Burkholderia cepacia lipase (BC-lipase). The spores that were resilient to stresses during material processing were mixed with poly(caprolactone) to produce living plastics in various formats. Spore incorporation did not compromise the physical properties of the materials. Spore recovery was triggered by eroding the plastic surface, after which the BC-lipase released by the germinated cells caused near-complete depolymerization of the polymer matrix. This study showcases a method for fabricating green plastics that can function when the spores are latent and decay when the spores are activated and sheds light on the development of materials for sustainability.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"31 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013811","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