Moisés Maestro-López, Tat Cheung Cheng, Jimena Muntaner, Margarita Menéndez, Melissa Alonso, Andreas Schweitzer, Masato Ishizaka, Robert J. Tomko Jr., Jorge Cuéllar, José María Valpuesta, Eri Sakata
Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26S proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo–electron microscopy structures of the Bag1-bound 26S proteasome, revealing unprecedented conformational rearrangements within the 19S regulatory particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA+ adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20S core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20S gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20S gate in the presence of Bag1, possibly bypassing the need for ubiquitination.
{"title":"Structures of the 26S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer","authors":"Moisés Maestro-López, Tat Cheung Cheng, Jimena Muntaner, Margarita Menéndez, Melissa Alonso, Andreas Schweitzer, Masato Ishizaka, Robert J. Tomko Jr., Jorge Cuéllar, José María Valpuesta, Eri Sakata","doi":"","DOIUrl":"","url":null,"abstract":"<div >Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26<i>S</i> proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo–electron microscopy structures of the Bag1-bound 26<i>S</i> proteasome, revealing unprecedented conformational rearrangements within the 19<i>S</i> regulatory particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA<sup>+</sup> adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20<i>S</i> core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20<i>S</i> gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20<i>S</i> gate in the presence of Bag1, possibly bypassing the need for ubiquitination.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nitric oxide synthase (NOS) is a widely studied multidomain redox enzyme that produces the key signaling molecule and cytotoxic agent nitric oxide (NO) for functions that range from mammalian vasodilation to prokaryotic antibiotic resistance. NOS enzymes from metazoans and cyanobacteria rely on dynamic associations of their oxygenase and coupled diflavin reductase domains that have largely evaded detailed structural characterization. Cryo–electron microscopy studies of a representative dimeric six-domain Synechococcus NOS reveal the architecture of the full-length enzyme, which contains an unusual regulatory C2 domain, and additional nitric oxide dioxygenase (NOD) and pseudoglobin modules. Five distinct structural states depict how pterin binding couples to tight and loose oxygenase conformations and how the Ca2+-sensitive C2 domain moves over 85 angstroms to alternatively regulate either the NOS or NOD heme center. The extended carboxyl-terminal tail and its dynamic interactions highlight an added layer of regulation required by multidomain NOSs compared to other diflavin reductases.
{"title":"Structure and dynamics of a multidomain nitric oxide synthase regulated by a C2 domain","authors":"Dhruva Nair, Brian R. Crane","doi":"","DOIUrl":"","url":null,"abstract":"<div >Nitric oxide synthase (NOS) is a widely studied multidomain redox enzyme that produces the key signaling molecule and cytotoxic agent nitric oxide (NO) for functions that range from mammalian vasodilation to prokaryotic antibiotic resistance. NOS enzymes from metazoans and cyanobacteria rely on dynamic associations of their oxygenase and coupled diflavin reductase domains that have largely evaded detailed structural characterization. Cryo–electron microscopy studies of a representative dimeric six-domain <i>Synechococcus</i> NOS reveal the architecture of the full-length enzyme, which contains an unusual regulatory C2 domain, and additional nitric oxide dioxygenase (NOD) and pseudoglobin modules. Five distinct structural states depict how pterin binding couples to tight and loose oxygenase conformations and how the Ca<sup>2+</sup>-sensitive C2 domain moves over 85 angstroms to alternatively regulate either the NOS or NOD heme center. The extended carboxyl-terminal tail and its dynamic interactions highlight an added layer of regulation required by multidomain NOSs compared to other diflavin reductases.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Subhash B. Arya, Fatima Jordan-Javed, Kristen Loesel, Yehyun Choi, Samuel P. Collie, Lauren E. Hein, Brendon M. Baker, Euisik Yoon, Carole A. Parent
Efficient neutrophil chemotaxis requires the integration of mechanical forces and lipid-mediated signaling. While the signaling lipid leukotriene B4 (LTB4) reinforces cellular polarity, how mechanical cues regulate its production remains unclear. We now show that cytosolic phospholipase A2α (cPLA2α), which is essential for the synthesis of LTB4, functions as a nuclear curvosensor. cPLA2α responds to nuclear squeezing by localizing to ceramide-rich inner nuclear membrane microdomains and incorporating onto the exofacial surface of nuclear envelope–derived exosomes. This unique topology enables localized LTB4 synthesis, which synchronizes calcium spikes, promotes myosin light chain II phosphorylation, and sustains polarity and directional persistence after constriction. In neutrophils passing through tight spaces, cPLA2α activity drives the chemotactic response to nuclear squeezing by promoting exosomal LTB4 production and persistence after constriction. These findings uncover a cPLA2α-dependent mechanochemical axis linking nuclear architecture to chemotactic efficiency and offer alternative strategies to modulate inflammatory responses.
{"title":"cPLA2α targeting to exosomes connects nuclear deformation to LTB4-signaling during neutrophil chemotaxis","authors":"Subhash B. Arya, Fatima Jordan-Javed, Kristen Loesel, Yehyun Choi, Samuel P. Collie, Lauren E. Hein, Brendon M. Baker, Euisik Yoon, Carole A. Parent","doi":"","DOIUrl":"","url":null,"abstract":"<div >Efficient neutrophil chemotaxis requires the integration of mechanical forces and lipid-mediated signaling. While the signaling lipid leukotriene B4 (LTB<sub>4</sub>) reinforces cellular polarity, how mechanical cues regulate its production remains unclear. We now show that cytosolic phospholipase A2α (cPLA<sub>2</sub>α), which is essential for the synthesis of LTB<sub>4</sub>, functions as a nuclear curvosensor. cPLA<sub>2</sub>α responds to nuclear squeezing by localizing to ceramide-rich inner nuclear membrane microdomains and incorporating onto the exofacial surface of nuclear envelope–derived exosomes. This unique topology enables localized LTB<sub>4</sub> synthesis, which synchronizes calcium spikes, promotes myosin light chain II phosphorylation, and sustains polarity and directional persistence after constriction. In neutrophils passing through tight spaces, cPLA<sub>2</sub>α activity drives the chemotactic response to nuclear squeezing by promoting exosomal LTB<sub>4</sub> production and persistence after constriction. These findings uncover a cPLA<sub>2</sub>α-dependent mechanochemical axis linking nuclear architecture to chemotactic efficiency and offer alternative strategies to modulate inflammatory responses.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Selective attention enables animals and humans to prioritize behaviorally relevant stimuli among competing sensory inputs. Although the basal forebrain (BF) is known to modulate cortical activity and support attention, it remains unclear whether BF activity directly conveys an attention signal. Here, we show that selective attention to auditory and visual stimuli converges onto a shared population of noncholinergic BF neurons. Using a cross-modal task where rats rapidly switched attention between modalities, we found that these neurons responded strongly to attended targets but weakly to the same stimuli when ignored, regardless of modality. These effects closely tracked both task-driven and spontaneous attention shifts on a single-trial basis. Moreover, BF responses reflected the linear summation of attended and ignored inputs, suggesting that sensory streams are filtered in parallel before converging in the BF. These findings suggest that the BF may serve as a subcortical hub integrating attention signals across modalities to guide adaptive behavior.
{"title":"Selective attention to auditory and visual modalities converges onto noncholinergic basal forebrain neurons","authors":"Sz-Wen Liu, Shih-Chieh Lin","doi":"","DOIUrl":"","url":null,"abstract":"<div >Selective attention enables animals and humans to prioritize behaviorally relevant stimuli among competing sensory inputs. Although the basal forebrain (BF) is known to modulate cortical activity and support attention, it remains unclear whether BF activity directly conveys an attention signal. Here, we show that selective attention to auditory and visual stimuli converges onto a shared population of noncholinergic BF neurons. Using a cross-modal task where rats rapidly switched attention between modalities, we found that these neurons responded strongly to attended targets but weakly to the same stimuli when ignored, regardless of modality. These effects closely tracked both task-driven and spontaneous attention shifts on a single-trial basis. Moreover, BF responses reflected the linear summation of attended and ignored inputs, suggesting that sensory streams are filtered in parallel before converging in the BF. These findings suggest that the BF may serve as a subcortical hub integrating attention signals across modalities to guide adaptive behavior.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li-Kun Yang, Qishu Qin, Jin Zhang, Ziyu Zhang, Haiyan Yu, Chengtian Zhao, Bo Dong
Settlement of marine invertebrate larvae at suitable sites for metamorphosis, growth, and reproduction is crucial for propagating populations, but often causes ecological problems such as bioinvasion and biofouling. Chemosensation plays an essential role in larval settlement preferences. However, the mechanisms for sensing chemical cues underlying these preferences remain unknown. Using urochordate ascidian larvae, the prominent marine fouling organisms affecting coastal ecosystems, we explored the mechanism of larval chemosensation and its role in settlement preference. Here, we identified taurine, a specific sulfur-containing amino acid secreted from marine adult animals, as a chemical attractant for ascidian larvae to locate salubrious environments for metamorphosis. Taurine stimulates primary sensory neurons within larval papillae, and this neuronal excitation is integrated in the simple brain (also known as sensory vesicle) to elicit chemoattraction and attachment of swimming larvae. We discuss the implications of this study in the emerging field of marine Eco-Evo-Devo research by establishing a model system for understanding developmental mechanisms in the context of marine ecosystems and aquaculture. Of interest is the potential development of antifouling strategies by targeting taurine chemosensation.
{"title":"Taurine-driven chemotaxis and metamorphosis in ascidian tadpole larvae","authors":"Li-Kun Yang, Qishu Qin, Jin Zhang, Ziyu Zhang, Haiyan Yu, Chengtian Zhao, Bo Dong","doi":"","DOIUrl":"","url":null,"abstract":"<div >Settlement of marine invertebrate larvae at suitable sites for metamorphosis, growth, and reproduction is crucial for propagating populations, but often causes ecological problems such as bioinvasion and biofouling. Chemosensation plays an essential role in larval settlement preferences. However, the mechanisms for sensing chemical cues underlying these preferences remain unknown. Using urochordate ascidian larvae, the prominent marine fouling organisms affecting coastal ecosystems, we explored the mechanism of larval chemosensation and its role in settlement preference. Here, we identified taurine, a specific sulfur-containing amino acid secreted from marine adult animals, as a chemical attractant for ascidian larvae to locate salubrious environments for metamorphosis. Taurine stimulates primary sensory neurons within larval papillae, and this neuronal excitation is integrated in the simple brain (also known as sensory vesicle) to elicit chemoattraction and attachment of swimming larvae. We discuss the implications of this study in the emerging field of marine Eco-Evo-Devo research by establishing a model system for understanding developmental mechanisms in the context of marine ecosystems and aquaculture. Of interest is the potential development of antifouling strategies by targeting taurine chemosensation.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lei Yu, Shixiong Zhang, Liang Liu, Di Li, Yongli Cai, Chenxin Wu, Lei Hua, Haiyang Li, Dehui Deng, Ping Chen, Zhenfeng Xi, Jianping Guo, Junnian Wei
Directly converting dinitrogen (N 2 ) into valuable nitrogen-containing compounds remains an enduring challenge in chemical synthesis. Here, we report the direct cyanation of aromatic substrates using N 2 and methane (CH 4 ) at atmospheric pressure facilitated by a custom-built, air-free dielectric barrier discharge (DBD) plasma system. A broad range of aromatic compounds, including benzene, were successfully transformed into their corresponding aromatic nitriles. Both experimental and computational evidence suggested that the reaction proceeds primarily via the in situ generation of •CN radicals from N 2 and CH 4 within the plasma zone. Subsequent radical addition to aromatic rings allowed the one-pot formation of aryl nitriles. This approach represents a major advancement in dinitrogen-based organic methodologies, providing an efficient alternative to conventional cyanation methods that heavily rely on lengthy synthetic routes and hazardous cyanide reagents.
{"title":"Direct cyanation of aromatic rings using dinitrogen and methane promoted by nonthermal plasma","authors":"Lei Yu, Shixiong Zhang, Liang Liu, Di Li, Yongli Cai, Chenxin Wu, Lei Hua, Haiyang Li, Dehui Deng, Ping Chen, Zhenfeng Xi, Jianping Guo, Junnian Wei","doi":"10.1126/sciadv.ady3414","DOIUrl":"https://doi.org/10.1126/sciadv.ady3414","url":null,"abstract":"Directly converting dinitrogen (N <jats:sub>2</jats:sub> ) into valuable nitrogen-containing compounds remains an enduring challenge in chemical synthesis. Here, we report the direct cyanation of aromatic substrates using N <jats:sub>2</jats:sub> and methane (CH <jats:sub>4</jats:sub> ) at atmospheric pressure facilitated by a custom-built, air-free dielectric barrier discharge (DBD) plasma system. A broad range of aromatic compounds, including benzene, were successfully transformed into their corresponding aromatic nitriles. Both experimental and computational evidence suggested that the reaction proceeds primarily via the in situ generation of •CN radicals from N <jats:sub>2</jats:sub> and CH <jats:sub>4</jats:sub> within the plasma zone. Subsequent radical addition to aromatic rings allowed the one-pot formation of aryl nitriles. This approach represents a major advancement in dinitrogen-based organic methodologies, providing an efficient alternative to conventional cyanation methods that heavily rely on lengthy synthetic routes and hazardous cyanide reagents.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"37 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaohan Song, Yuhan Lu, Xinlong Guo, Yanan Zheng, He Huang
Lysine acetoacetylation (Kacac) driven by metabolite acetoacetic acid represents a molecular mechanism by which ketone bodies regulate cellular functions beyond energy provision. However, comprehensive characterization of Kacac has been hindered by technical limitations in detection and functional validation. Here, we report an integrated platform for systematic Kacac investigation. Exploiting the unique reactive ketone carbonyl moiety, we developed Aca-Bio, a hydroxylamine-based probe enabling specific enrichment of Kacac peptides through ketone-targeted covalent labeling and pH-controlled reversible enrichment. Application to mouse liver identified 260 Kacac sites across 125 proteins, revealing notable enrichment in metabolic pathways. Concurrently, we established a genetic code expansion system enabling site-specific Kacac incorporation. Using this approach, we demonstrated that K310acac in HMGCS2 substantially attenuates catalytic activity through impaired substrate binding. This dual-platform approach establishes a comprehensive framework for global profiling and site-specific functional characterization of Kacac, thereby facilitating systematic exploration of its physiological roles and pathological implications.
{"title":"Covalent capture and genetic code expansion enables chemoproteomic profiling and functional characterization of lysine acetoacetylation","authors":"Xiaohan Song, Yuhan Lu, Xinlong Guo, Yanan Zheng, He Huang","doi":"10.1126/sciadv.aeb5106","DOIUrl":"https://doi.org/10.1126/sciadv.aeb5106","url":null,"abstract":"Lysine acetoacetylation (Kacac) driven by metabolite acetoacetic acid represents a molecular mechanism by which ketone bodies regulate cellular functions beyond energy provision. However, comprehensive characterization of Kacac has been hindered by technical limitations in detection and functional validation. Here, we report an integrated platform for systematic Kacac investigation. Exploiting the unique reactive ketone carbonyl moiety, we developed Aca-Bio, a hydroxylamine-based probe enabling specific enrichment of Kacac peptides through ketone-targeted covalent labeling and pH-controlled reversible enrichment. Application to mouse liver identified 260 Kacac sites across 125 proteins, revealing notable enrichment in metabolic pathways. Concurrently, we established a genetic code expansion system enabling site-specific Kacac incorporation. Using this approach, we demonstrated that K310acac in HMGCS2 substantially attenuates catalytic activity through impaired substrate binding. This dual-platform approach establishes a comprehensive framework for global profiling and site-specific functional characterization of Kacac, thereby facilitating systematic exploration of its physiological roles and pathological implications.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"20 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traditional petroleum distillation faces high energy demands, necessitating innovative alternatives like membrane separation. This study presents a breakthrough in dual-range and precise pore size modulation of metal-organic frameworks (MOFs) through a ligand functionalization strategy. By tailoring steric configurations and spatial orientations of light-responsive azobenzene groups, we achieved broad-range pore tuning (0.41 to 0.68 nanometers) via functional group length variation, coupled with subnanometer precision through reversible trans-to-cis photoisomerization. Four representative branched alkanes were selected to validate the MOF’s high selectivity. Results showed its capacity to generate a constant carbon-atom-count–dependent permeation gradient, realizing a four-step sequential separation that increased C 6 H 14 purity from 25 to 92.2%. This synergistic approach uniquely combines large-scale pore adjustment with dynamic fine-tuning, decoupling separation efficiency from energy-intensive processes. The membranes’ structural stability and reversible light responsiveness further highlight their potential for sustainable hydrocarbon processing. By integrating molecular design with stimuli-responsive control, this work advances MOF-based membranes as a transformative solution for energy-efficient petroleum fractionation and precise molecular sieving.
{"title":"Precise modulation of MOF pore structures via functional group dimensions and spatial configuration for membrane separation","authors":"Weijian Sun, Kaicheng Yang, Yifan Zhao, Liping Sun, Qingchi Xu, Jian Weng, Jun Xu","doi":"10.1126/sciadv.adz7972","DOIUrl":"https://doi.org/10.1126/sciadv.adz7972","url":null,"abstract":"Traditional petroleum distillation faces high energy demands, necessitating innovative alternatives like membrane separation. This study presents a breakthrough in dual-range and precise pore size modulation of metal-organic frameworks (MOFs) through a ligand functionalization strategy. By tailoring steric configurations and spatial orientations of light-responsive azobenzene groups, we achieved broad-range pore tuning (0.41 to 0.68 nanometers) via functional group length variation, coupled with subnanometer precision through reversible trans-to-cis photoisomerization. Four representative branched alkanes were selected to validate the MOF’s high selectivity. Results showed its capacity to generate a constant carbon-atom-count–dependent permeation gradient, realizing a four-step sequential separation that increased C <jats:sub>6</jats:sub> H <jats:sub>14</jats:sub> purity from 25 to 92.2%. This synergistic approach uniquely combines large-scale pore adjustment with dynamic fine-tuning, decoupling separation efficiency from energy-intensive processes. The membranes’ structural stability and reversible light responsiveness further highlight their potential for sustainable hydrocarbon processing. By integrating molecular design with stimuli-responsive control, this work advances MOF-based membranes as a transformative solution for energy-efficient petroleum fractionation and precise molecular sieving.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"30 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oluwaseun D. Akanbi, Michael L. Felder, Daniel Kupor, Jiachen Feng, Luana Janaína de Campos, Lisa J. Bain, Crystal Sanchez, Hanieh Safari, Thi Vo, Martin Conda-Sheridan, Omolola Eniola-Adefeso
Steroids, specifically bile salts and corticosteroids, treat bile synthesis disorders, liver dysfunction, and inflammation. However, these water-soluble steroid drugs are rapidly cleared from the desired sites of action in the body, necessitating multiple doses. Therefore, the development of particle-based steroid medications that offer elongated therapeutic activity is of paramount medical importance. Accordingly, steroid microparticles were developed via three fabrication processes in this work, where a metal or an organic acid facilitates steroid microparticle formation. Particles fabricated using these methods exhibit consistent shape, size, and crystallinity. Furthermore, results from our coarse-grained computational model show that hydrogen bonding dictates steroid monomer-monomer interactions that determine overall particle shape and size. In addition, we demonstrate the ability to induce steroid particle formation and tune the morphology of steroid drug particles by replacing the C21 side group (tail) with chemical analogs. Thus, this study opens opportunities for the clinical translation of particle-based steroid therapeutics as an alternative to the current steroid drug formulations.
{"title":"Engineering controlled-release steroid therapeutics: fabrication and molecular design of self-assembled microparticles","authors":"Oluwaseun D. Akanbi, Michael L. Felder, Daniel Kupor, Jiachen Feng, Luana Janaína de Campos, Lisa J. Bain, Crystal Sanchez, Hanieh Safari, Thi Vo, Martin Conda-Sheridan, Omolola Eniola-Adefeso","doi":"10.1126/sciadv.adz7078","DOIUrl":"https://doi.org/10.1126/sciadv.adz7078","url":null,"abstract":"Steroids, specifically bile salts and corticosteroids, treat bile synthesis disorders, liver dysfunction, and inflammation. However, these water-soluble steroid drugs are rapidly cleared from the desired sites of action in the body, necessitating multiple doses. Therefore, the development of particle-based steroid medications that offer elongated therapeutic activity is of paramount medical importance. Accordingly, steroid microparticles were developed via three fabrication processes in this work, where a metal or an organic acid facilitates steroid microparticle formation. Particles fabricated using these methods exhibit consistent shape, size, and crystallinity. Furthermore, results from our coarse-grained computational model show that hydrogen bonding dictates steroid monomer-monomer interactions that determine overall particle shape and size. In addition, we demonstrate the ability to induce steroid particle formation and tune the morphology of steroid drug particles by replacing the C21 side group (tail) with chemical analogs. Thus, this study opens opportunities for the clinical translation of particle-based steroid therapeutics as an alternative to the current steroid drug formulations.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"24 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Moisés Maestro-López, Tat Cheung Cheng, Jimena Muntaner, Margarita Menéndez, Melissa Alonso, Andreas Schweitzer, Masato Ishizaka, Robert J. Tomko, Jorge Cuéllar, José María Valpuesta, Eri Sakata
Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26 S proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo–electron microscopy structures of the Bag1-bound 26 S proteasome, revealing unprecedented conformational rearrangements within the 19 S regulatory particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA + adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20 S core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20 S gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20 S gate in the presence of Bag1, possibly bypassing the need for ubiquitination.
{"title":"Structures of the 26 S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer","authors":"Moisés Maestro-López, Tat Cheung Cheng, Jimena Muntaner, Margarita Menéndez, Melissa Alonso, Andreas Schweitzer, Masato Ishizaka, Robert J. Tomko, Jorge Cuéllar, José María Valpuesta, Eri Sakata","doi":"10.1126/sciadv.adz3026","DOIUrl":"https://doi.org/10.1126/sciadv.adz3026","url":null,"abstract":"Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26 <jats:italic toggle=\"yes\">S</jats:italic> proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo–electron microscopy structures of the Bag1-bound 26 <jats:italic toggle=\"yes\">S</jats:italic> proteasome, revealing unprecedented conformational rearrangements within the 19 <jats:italic toggle=\"yes\">S</jats:italic> regulatory particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA <jats:sup>+</jats:sup> adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20 <jats:italic toggle=\"yes\">S</jats:italic> core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20 <jats:italic toggle=\"yes\">S</jats:italic> gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20 <jats:italic toggle=\"yes\">S</jats:italic> gate in the presence of Bag1, possibly bypassing the need for ubiquitination.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"20 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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