Pub Date : 2026-01-16DOI: 10.1038/s41589-025-02085-x
Markus Müller, Konstantin Niemeyer, Navin K. Ojha, Sebastian A. Porav, Deivanayagabarathy Vinayagam, Nicole Urban, Fanny Büchau, Katharina Oleinikov, Mazen Makke, Claudia C. Bauer, Aidan V. Johnson, Stephen P. Muench, Frank Zufall, Dieter Bruns, Yvonne Schwarz, Stefan Raunser, Trese Leinders-Zufall, Robin S. Bon, Michael Schaefer, Oliver Thorn-Seshold
Precisely probing the endogenous roles of target proteins is crucial for biological research. Photochemical tools can be photoactuated with high spatiotemporal resolution but often they are unreliable in vivo because spatiotemporal variations of reagent concentration result in inhomogeneous bioactivity. We now describe ideal efficacy photoswitching, a paradigm that internally compensates for reagent concentration by self-competitive binding, allowing purely wavelength-dependent chromocontrol over bioactivity that is consistent from cell culture to deep tissues. We demonstrate this with photoswitches for endogenous transient receptor potential (TRP) C4 and C5 ion channels, reproducibly delivering strong agonism under 360-nm illumination, weak agonism under 385-nm illumination and strong antagonism under 440-nm illumination. These ligands unlock a range of high-precision investigations in TRP biology, from neuronal activity to exocytosis, reproductive signaling and smooth muscle contractility. The ideal efficacy photoswitching paradigm should also unlock high-performance chromocontrol over a wide range of sensory or signaling channels and receptors even in vivo. Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.
{"title":"Ideal efficacy photoswitching for chromocontrol of TRPC4/5 channel functions in live tissues","authors":"Markus Müller, Konstantin Niemeyer, Navin K. Ojha, Sebastian A. Porav, Deivanayagabarathy Vinayagam, Nicole Urban, Fanny Büchau, Katharina Oleinikov, Mazen Makke, Claudia C. Bauer, Aidan V. Johnson, Stephen P. Muench, Frank Zufall, Dieter Bruns, Yvonne Schwarz, Stefan Raunser, Trese Leinders-Zufall, Robin S. Bon, Michael Schaefer, Oliver Thorn-Seshold","doi":"10.1038/s41589-025-02085-x","DOIUrl":"10.1038/s41589-025-02085-x","url":null,"abstract":"Precisely probing the endogenous roles of target proteins is crucial for biological research. Photochemical tools can be photoactuated with high spatiotemporal resolution but often they are unreliable in vivo because spatiotemporal variations of reagent concentration result in inhomogeneous bioactivity. We now describe ideal efficacy photoswitching, a paradigm that internally compensates for reagent concentration by self-competitive binding, allowing purely wavelength-dependent chromocontrol over bioactivity that is consistent from cell culture to deep tissues. We demonstrate this with photoswitches for endogenous transient receptor potential (TRP) C4 and C5 ion channels, reproducibly delivering strong agonism under 360-nm illumination, weak agonism under 385-nm illumination and strong antagonism under 440-nm illumination. These ligands unlock a range of high-precision investigations in TRP biology, from neuronal activity to exocytosis, reproductive signaling and smooth muscle contractility. The ideal efficacy photoswitching paradigm should also unlock high-performance chromocontrol over a wide range of sensory or signaling channels and receptors even in vivo. Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"180-191"},"PeriodicalIF":13.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41589-025-02085-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986231","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}
Pub Date : 2026-01-16DOI: 10.1038/s41589-025-02087-9
Jana Volarić, Wiktor Szymanski
Ideal efficacy photoswitching is introduced as a concept in controlling protein activity with light. Largely independent of the concentration of a light-responsive compound, it enables TRPC4 and TRPC5 channels to be precisely agonized or antagonized depending on the color of light used.
{"title":"Pick a color to control TRP channels","authors":"Jana Volarić, Wiktor Szymanski","doi":"10.1038/s41589-025-02087-9","DOIUrl":"10.1038/s41589-025-02087-9","url":null,"abstract":"Ideal efficacy photoswitching is introduced as a concept in controlling protein activity with light. Largely independent of the concentration of a light-responsive compound, it enables TRPC4 and TRPC5 channels to be precisely agonized or antagonized depending on the color of light used.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"163-164"},"PeriodicalIF":13.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986232","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}
Pub Date : 2026-01-13DOI: 10.1038/s41589-025-02131-8
Lu Hu, Jinyu Lin, Liping Sun, Alison M. Berezuk, Katharine S. Tuttle, Xing Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Pan Li, Yang Sun, Lisheng Ni, Jianan Zhang, Dazhi Tan, Hiroaki Wakimoto, Daniel P. Cahill, Xiaochen Bai, Xuelian Luo, John M. Asara, Sriram Subramaniam, Yibing Shan, Xu Wu
Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.
{"title":"Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells","authors":"Lu Hu, Jinyu Lin, Liping Sun, Alison M. Berezuk, Katharine S. Tuttle, Xing Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Pan Li, Yang Sun, Lisheng Ni, Jianan Zhang, Dazhi Tan, Hiroaki Wakimoto, Daniel P. Cahill, Xiaochen Bai, Xuelian Luo, John M. Asara, Sriram Subramaniam, Yibing Shan, Xu Wu","doi":"10.1038/s41589-025-02131-8","DOIUrl":"https://doi.org/10.1038/s41589-025-02131-8","url":null,"abstract":"Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"385 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956335","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}
Pub Date : 2026-01-13DOI: 10.1038/s41589-025-02125-6
{"title":"Complexoform-specific ligands that modulate the pleiotropic methyltransferase adaptor TRMT112.","authors":"","doi":"10.1038/s41589-025-02125-6","DOIUrl":"https://doi.org/10.1038/s41589-025-02125-6","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"14 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961607","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}
The Warburg effect leads to increased lactate production and promotes cancer progression but the underlying mechanisms remain unclear. Here, we found that lactate activates the MAPK pathway through ERK lactylation, which promotes cancer progression. We identified GCN5 as the lactyltransferase responsible for ERK lactylation. Activated ERK phosphorylates GCN5, increasing its lactyltransferase activity toward ERK and establishing a positive feedback loop that amplifies lactate-mediated cancer progression. We provide evidence that lactylation of ERK at residue K231 weakens its interaction with MEK, thereby promoting ERK dimerization and activation. We developed a cell-penetrating peptide that specifically inhibits ERK lactylation. This peptide impairs tumor growth in KRAS-mutant cancer models. Taken together, our findings reveal a molecular mechanism by which lactate accelerates cancer progression through the ERK–GCN5 lactylation–phosphorylation cascade and suggest a strategy to disrupt ERK lactylation in RAS–ERK-driven cancers.
{"title":"GCN5–ERK lactylation–phosphorylation loop amplifies lactate-driven cancer progression","authors":"Bingsong Huang, Mingpeng Jin, Gaofeng Cui, Zhe Wang, Feng Wang, Mu Chen, Lei Zhu, Yunxuan Li, Xiaoning Yang, Rui Li, Jinhuan Wu, Linhui Zhai, Yiming He, Jie Yang, Xin Ding, Qianwen Wang, Zhen Xv, Yaobing Ouyang, Jiale Li, Yangbohui Yang, Ke Li, Zhenkun Lou, Georges Mer, Jing Zhang, Yuping Chen, Jian Yuan, Chunlong Zhong","doi":"10.1038/s41589-025-02107-8","DOIUrl":"https://doi.org/10.1038/s41589-025-02107-8","url":null,"abstract":"The Warburg effect leads to increased lactate production and promotes cancer progression but the underlying mechanisms remain unclear. Here, we found that lactate activates the MAPK pathway through ERK lactylation, which promotes cancer progression. We identified GCN5 as the lactyltransferase responsible for ERK lactylation. Activated ERK phosphorylates GCN5, increasing its lactyltransferase activity toward ERK and establishing a positive feedback loop that amplifies lactate-mediated cancer progression. We provide evidence that lactylation of ERK at residue K231 weakens its interaction with MEK, thereby promoting ERK dimerization and activation. We developed a cell-penetrating peptide that specifically inhibits ERK lactylation. This peptide impairs tumor growth in KRAS-mutant cancer models. Taken together, our findings reveal a molecular mechanism by which lactate accelerates cancer progression through the ERK–GCN5 lactylation–phosphorylation cascade and suggest a strategy to disrupt ERK lactylation in RAS–ERK-driven cancers.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"29 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956336","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}
Protein ubiquitination critically regulates biological processes through both proteolytic and nonproteolytic mechanisms. While classically known for protein degradation, ubiquitination also modulates enzymatic activity. However, current mechanisms of ubiquitination-mediated enzymatic modulation are spatially constrained near enzyme-substrate interfaces. Here, we report a unique ubiquitination-mediated regulatory paradigm that activates the Polycomb repressive deubiquitinase (PR-DUB) complex from a site distal to the enzyme-substrate interface. We found that ASXL1 K351 monoubiquitination promotes nucleosomal H2AK119Ub deubiquitination by stabilizing the PR-DUB catalytic pocket, thereby increasing catalytic velocity (Vmax) without affecting substrate affinity (Km). Structurally, ubiquitin at ASXL1 K351 bridges the BAP1 and ASXL1 subunits, functioning as a cross-bracing 'glue' that constrains their conformational dynamics without altering the nucleosome-binding interface. Molecular dynamics and hydrogen-deuterium exchange mass spectrometry revealed that this modification locks PR-DUB in a catalytic state poised for substrate cleavage. This study reveals a unique ubiquitin function of intersubunit fastening through a molecular glue effect and clarifies the mechanism of PR-DUB activation.
{"title":"Unique gluing effect of ASXL1 K351 monoubiquitination stimulates the PR-DUB activity.","authors":"Tianyi Zhang,Jiqing Zheng,Zebing Tong,Zhiheng Deng,Zaozhen He,Xiangwei Wu,Miao Wang,Yunxiang Du,Ziyu Xu,Shixian Tao,Shizhang Wan,Xiaolin Tian,Haiteng Deng,Man Pan,Huasong Ai,Lei Liu","doi":"10.1038/s41589-025-02126-5","DOIUrl":"https://doi.org/10.1038/s41589-025-02126-5","url":null,"abstract":"Protein ubiquitination critically regulates biological processes through both proteolytic and nonproteolytic mechanisms. While classically known for protein degradation, ubiquitination also modulates enzymatic activity. However, current mechanisms of ubiquitination-mediated enzymatic modulation are spatially constrained near enzyme-substrate interfaces. Here, we report a unique ubiquitination-mediated regulatory paradigm that activates the Polycomb repressive deubiquitinase (PR-DUB) complex from a site distal to the enzyme-substrate interface. We found that ASXL1 K351 monoubiquitination promotes nucleosomal H2AK119Ub deubiquitination by stabilizing the PR-DUB catalytic pocket, thereby increasing catalytic velocity (Vmax) without affecting substrate affinity (Km). Structurally, ubiquitin at ASXL1 K351 bridges the BAP1 and ASXL1 subunits, functioning as a cross-bracing 'glue' that constrains their conformational dynamics without altering the nucleosome-binding interface. Molecular dynamics and hydrogen-deuterium exchange mass spectrometry revealed that this modification locks PR-DUB in a catalytic state poised for substrate cleavage. This study reveals a unique ubiquitin function of intersubunit fastening through a molecular glue effect and clarifies the mechanism of PR-DUB activation.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"35 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937893","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}
Temozolomide is a standard-of-care therapeutic agent for glioblastoma. However, persons who initially respond well often experience a notable reduction in efficacy over time, with the underlying mechanisms remaining unclear. Here we demonstrate that the reduced response to temozolomide correlates with decreased chromatin accessibility, marked by reduced H3K27ac modification and alterations in chromatin loops. Mechanistically, temozolomide treatment upregulates histone deacetylase 1 (HDAC1) expression. Intriguingly, increased HDAC1 forms condensates independently of its deacetylase function. These condensates arise from multivalent interactions within the intrinsically disordered region and specific interactions with CCCTC-binding factor (CTCF), facilitating resistance to temozolomide by promoting the assembly of DNA repair complexes, even in the absence of direct deacetylase activity of HDAC1. Through phase-separation-based screening, we identified resminostat as an effective disruptor of HDAC1-CTCF condensates, thereby restoring temozolomide sensitivity in patient-derived xenograft models. Our findings introduce deacetylase-independent HDAC1 condensation as a distinct mechanism regulating temozolomide response, providing valuable insights into potential therapeutic strategies.
{"title":"Deacetylase-independent HDAC1 condensation defines temozolomide response in glioblastoma.","authors":"Qinkai Zhang,Ru Qiu,Bing Lu,Jinhong Wang,Jizhao Cao,Hongni Zhu,Meng Huang,Wenyong Long,Ke Fang,Chuanxia Zhang,Fuxi Li,Wei Shi,Qing Liu,Yiming Li,Peng Dong,Wei Zhao","doi":"10.1038/s41589-025-02123-8","DOIUrl":"https://doi.org/10.1038/s41589-025-02123-8","url":null,"abstract":"Temozolomide is a standard-of-care therapeutic agent for glioblastoma. However, persons who initially respond well often experience a notable reduction in efficacy over time, with the underlying mechanisms remaining unclear. Here we demonstrate that the reduced response to temozolomide correlates with decreased chromatin accessibility, marked by reduced H3K27ac modification and alterations in chromatin loops. Mechanistically, temozolomide treatment upregulates histone deacetylase 1 (HDAC1) expression. Intriguingly, increased HDAC1 forms condensates independently of its deacetylase function. These condensates arise from multivalent interactions within the intrinsically disordered region and specific interactions with CCCTC-binding factor (CTCF), facilitating resistance to temozolomide by promoting the assembly of DNA repair complexes, even in the absence of direct deacetylase activity of HDAC1. Through phase-separation-based screening, we identified resminostat as an effective disruptor of HDAC1-CTCF condensates, thereby restoring temozolomide sensitivity in patient-derived xenograft models. Our findings introduce deacetylase-independent HDAC1 condensation as a distinct mechanism regulating temozolomide response, providing valuable insights into potential therapeutic strategies.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"47 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937889","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}
Lipid droplets (LDs) dynamically interact with other organelles, such as mitochondria, in surveillance of cellular metabolic homeostasis. The transient nature of LDs, however, poses technical challenges to snapshot molecular information underlying these interactions. Herein, we present a small-molecule-based photocatalytic protein proximity labeling method (named LipoID) to enable in situ labeling, capturing and profiling of the LD-interacting proteome. This method is enabled by a set of LD-targeting probes designed to catalyze protein modifications nearby LDs using nucleophilic substrates. Profiled by liquid chromatography-tandem mass spectrometry, LipoID identifies tethered interorganellar interactions, particularly with mitochondria, in addition to reliable capture of validated LD biomarkers (for example, perilipins (PLINs)). Coupled with comparative proteomics, LipoID discovers mitochondrial voltage-dependent anion channel 3 as a potential regulator of LD-mitochondria proximity through interacting with PLIN3 on LDs. Further metabolomics analysis suggested remodeled lipid metabolism in line with the LD-mitochondria interaction. Together, LipoID enables in situ profiling of the LD interactome and reveals interorganellar regulation.
{"title":"LipoID profiles lipid droplet interactions and identifies interorganelle regulators.","authors":"Hengke Guo,Wang Wan,Yanan Huang,Nan Zhao,Ci Wu,Bowen Zhong,Rui Sun,Huan Feng,Jing Yan,Di Shen,Xuepeng Dong,Qun Zhao,Xin Zhang,Lihua Zhang,Yu Liu","doi":"10.1038/s41589-025-02127-4","DOIUrl":"https://doi.org/10.1038/s41589-025-02127-4","url":null,"abstract":"Lipid droplets (LDs) dynamically interact with other organelles, such as mitochondria, in surveillance of cellular metabolic homeostasis. The transient nature of LDs, however, poses technical challenges to snapshot molecular information underlying these interactions. Herein, we present a small-molecule-based photocatalytic protein proximity labeling method (named LipoID) to enable in situ labeling, capturing and profiling of the LD-interacting proteome. This method is enabled by a set of LD-targeting probes designed to catalyze protein modifications nearby LDs using nucleophilic substrates. Profiled by liquid chromatography-tandem mass spectrometry, LipoID identifies tethered interorganellar interactions, particularly with mitochondria, in addition to reliable capture of validated LD biomarkers (for example, perilipins (PLINs)). Coupled with comparative proteomics, LipoID discovers mitochondrial voltage-dependent anion channel 3 as a potential regulator of LD-mitochondria proximity through interacting with PLIN3 on LDs. Further metabolomics analysis suggested remodeled lipid metabolism in line with the LD-mitochondria interaction. Together, LipoID enables in situ profiling of the LD interactome and reveals interorganellar regulation.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"57 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937892","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}
Pub Date : 2026-01-09DOI: 10.1038/s41589-025-02130-9
Catherine A. Musselman, Tatiana G. Kutateladze
{"title":"Targeting epigenetic readers","authors":"Catherine A. Musselman, Tatiana G. Kutateladze","doi":"10.1038/s41589-025-02130-9","DOIUrl":"https://doi.org/10.1038/s41589-025-02130-9","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"47 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145938278","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}
Pub Date : 2026-01-09DOI: 10.1038/s41589-025-02128-3
Yuefeng Ma,Leshan Yang,Yantong Chen,Michael W Chen,Wen Yu,Yifan Dai
Engineering synthetic intrinsically disordered proteins (synIDPs) enables regulation of biomolecular condensation and protein solubility. However, limited understanding of how sequence-dependent interaction cooperativity relates to the fitness impacts of synIDPs on endogenous cellular processes constrains our design capability. Here, to circumvent this design challenge, we present a systematic directed evolution method for the evolution of synIDPs capable of mediating diverse phase behaviors in living cells. The selection methods allow us to evolve a toolbox of synIDPs with distinct phase behaviors and thermoresponsive features in living cells, leading to the evolution of synthetic condensates. The reverse-selection method further allows us to select synIDPs as solubility tags. We demonstrate the applications of the evolved synIDPs in protein circuits to (1) regulate intracellular protein activity and (2) reverse antibiotic resistance. Our systematic evolution and selection strategies provide a versatile platform for developing synIDPs for broad applications in synthetic biology and biotechnology.
{"title":"Directed evolution of functional intrinsically disordered proteins.","authors":"Yuefeng Ma,Leshan Yang,Yantong Chen,Michael W Chen,Wen Yu,Yifan Dai","doi":"10.1038/s41589-025-02128-3","DOIUrl":"https://doi.org/10.1038/s41589-025-02128-3","url":null,"abstract":"Engineering synthetic intrinsically disordered proteins (synIDPs) enables regulation of biomolecular condensation and protein solubility. However, limited understanding of how sequence-dependent interaction cooperativity relates to the fitness impacts of synIDPs on endogenous cellular processes constrains our design capability. Here, to circumvent this design challenge, we present a systematic directed evolution method for the evolution of synIDPs capable of mediating diverse phase behaviors in living cells. The selection methods allow us to evolve a toolbox of synIDPs with distinct phase behaviors and thermoresponsive features in living cells, leading to the evolution of synthetic condensates. The reverse-selection method further allows us to select synIDPs as solubility tags. We demonstrate the applications of the evolved synIDPs in protein circuits to (1) regulate intracellular protein activity and (2) reverse antibiotic resistance. Our systematic evolution and selection strategies provide a versatile platform for developing synIDPs for broad applications in synthetic biology and biotechnology.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"124 12 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937891","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}
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