Pub Date : 2026-03-05DOI: 10.1038/s41594-026-01769-9
Joshua B Sheetz,Srividya Chandrasekhar,Michael Rapé
As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
{"title":"Function and regulation of the mitochondrial stress response.","authors":"Joshua B Sheetz,Srividya Chandrasekhar,Michael Rapé","doi":"10.1038/s41594-026-01769-9","DOIUrl":"https://doi.org/10.1038/s41594-026-01769-9","url":null,"abstract":"As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Proteostasis in mammalian oocytes is vital for successful reproduction. The cytoplasmic lattices (CPLs) of oocytes store essential maternal proteins for early embryo development. Here we show that PADI6, a core component of CPLs, forms a conserved ternary complex that we term MPU for maternal PADI6-UHRF1-UBE2D. The MPU complex regulates protein ubiquitination during oocyte maturation and early embryogenesis. We determined the cryo-electron microscopy structure of MPU and show that 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly, revealing a potential molecular mechanism linking dysregulation of ubiquitination on oocytes to abnormal embryonic development. Mechanistically, PADI6, with the assistance of UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to relevant substrate proteins, thereby suppressing the ubiquitination cascade. Therefore, our findings implicate PADI6 in the regulation of proteostasis by controlling the ubiquitination cascade, expanding our understanding of PADI6-dependent regulation of oocyte maturation and early embryogenesis.
{"title":"The maternal PADI6-UHRF1-UBE2D complex regulates ubiquitination during oocyte maturation and embryogenesis.","authors":"Jinhong Li,Yuechao Lu,Zhili Xia,Pengliang Chi,Qianqian Qi,Sibei Liu,Sicheng Ju,Jialu Li,Zihan Zhang,Zhuo Han,Qingting Liu,Wenbo Meng,Jing Chen,Xiang Wang,Li Guo,Lei Li,Wei Huang,Lunzhi Dai,Junhong Han,Shaorong Gao,Dong Deng","doi":"10.1038/s41594-026-01758-y","DOIUrl":"https://doi.org/10.1038/s41594-026-01758-y","url":null,"abstract":"Proteostasis in mammalian oocytes is vital for successful reproduction. The cytoplasmic lattices (CPLs) of oocytes store essential maternal proteins for early embryo development. Here we show that PADI6, a core component of CPLs, forms a conserved ternary complex that we term MPU for maternal PADI6-UHRF1-UBE2D. The MPU complex regulates protein ubiquitination during oocyte maturation and early embryogenesis. We determined the cryo-electron microscopy structure of MPU and show that 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly, revealing a potential molecular mechanism linking dysregulation of ubiquitination on oocytes to abnormal embryonic development. Mechanistically, PADI6, with the assistance of UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to relevant substrate proteins, thereby suppressing the ubiquitination cascade. Therefore, our findings implicate PADI6 in the regulation of proteostasis by controlling the ubiquitination cascade, expanding our understanding of PADI6-dependent regulation of oocyte maturation and early embryogenesis.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"99 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-25DOI: 10.1038/s41594-026-01757-z
Youngseo Cheon, Erik Glen Alvstad, Denis Torre, Daniel Tu Quach, Jennifer Nguyen, Kwangbeom Hyun, Mingqi Zhou, Tianxiong Yu, Liang Liu, Yoseop Yoon, Fairlie Reese, Lauren Faraone, Yingcong Li, Frederick J. Arnold, Yesai S. Fstkchyan, Uttiya Basu, Evgeny Kvon, Enza Maria Valente, Jessica Sook Yuin Ho, Minji Byun, Ernesto Guccione, Yongsheng Shi, Zhiping Weng, Marcus Seldin, Ivan Marazzi
Transposable elements (TEs) in the human genome are the heritage of ancient parasitic infections. While most of human DNA comprises TEs and TE-derived elements, their repetitive nature poses technical challenges; thus, little is known about their positional identity and regulatory roles. Here, by integrating long-read and multidimensional transcriptional analyses, we investigate when, where and how TEs become part of a gene. We characterize how TE-derived isoforms change across mouse–human variation and how they are linked to gene regulatory networks controlling cell states during differentiation, organogenesis and health (aging and pathological states). Mechanistically, we identify an RNA degradation-dependent and splicing-dependent quality control mechanism that operates independently of conventional mechanisms of TE suppression, such as DNA methylation and heterochromatinization, and prevents TE-chimera expression and TE-induced cell differentiation. Overall, our findings unveil mechanisms by which viral-derived elements enhance transcriptome plasticity.
{"title":"Transposable element–gene chimera cartography, origination and role in enhancing transcriptome plasticity","authors":"Youngseo Cheon, Erik Glen Alvstad, Denis Torre, Daniel Tu Quach, Jennifer Nguyen, Kwangbeom Hyun, Mingqi Zhou, Tianxiong Yu, Liang Liu, Yoseop Yoon, Fairlie Reese, Lauren Faraone, Yingcong Li, Frederick J. Arnold, Yesai S. Fstkchyan, Uttiya Basu, Evgeny Kvon, Enza Maria Valente, Jessica Sook Yuin Ho, Minji Byun, Ernesto Guccione, Yongsheng Shi, Zhiping Weng, Marcus Seldin, Ivan Marazzi","doi":"10.1038/s41594-026-01757-z","DOIUrl":"https://doi.org/10.1038/s41594-026-01757-z","url":null,"abstract":"Transposable elements (TEs) in the human genome are the heritage of ancient parasitic infections. While most of human DNA comprises TEs and TE-derived elements, their repetitive nature poses technical challenges; thus, little is known about their positional identity and regulatory roles. Here, by integrating long-read and multidimensional transcriptional analyses, we investigate when, where and how TEs become part of a gene. We characterize how TE-derived isoforms change across mouse–human variation and how they are linked to gene regulatory networks controlling cell states during differentiation, organogenesis and health (aging and pathological states). Mechanistically, we identify an RNA degradation-dependent and splicing-dependent quality control mechanism that operates independently of conventional mechanisms of TE suppression, such as DNA methylation and heterochromatinization, and prevents TE-chimera expression and TE-induced cell differentiation. Overall, our findings unveil mechanisms by which viral-derived elements enhance transcriptome plasticity.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"128 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-25DOI: 10.1038/s41594-026-01775-x
M. Jasnauskaitė, J. Juozapaitis, T. Liegutė, R. Grigaitis, A. Skorupskaitė, W. Steinchen, A. Mikšys, L. Truncaitė, K. Kazlauskaitė, M. F. Torres Jiménez, S. Khochare, G. Dudas, G. Bange, L. Malinauskaitė, I. Songailienė, P. Pausch
{"title":"Author Correction: Structure and mechanism of antiphage retron Eco2","authors":"M. Jasnauskaitė, J. Juozapaitis, T. Liegutė, R. Grigaitis, A. Skorupskaitė, W. Steinchen, A. Mikšys, L. Truncaitė, K. Kazlauskaitė, M. F. Torres Jiménez, S. Khochare, G. Dudas, G. Bange, L. Malinauskaitė, I. Songailienė, P. Pausch","doi":"10.1038/s41594-026-01775-x","DOIUrl":"https://doi.org/10.1038/s41594-026-01775-x","url":null,"abstract":"","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"104 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-24DOI: 10.1038/s41594-026-01749-z
Irene Mota-Gómez, Juan Antonio Rodríguez, Shannon Dupont, Alicia Hurtado, Vanessa Cadenas, Leo Zuber, Iago Maceda, Oscar Lao, Johanna Jedamzick, Ralf Kühn, Scott Lacadie, Sara Alexandra García-Moreno, Miguel Torres, Francisca M. Real, Rafael D. Acemel, Blanche Capel, Marc A. Marti-Renom, Darío G. Lupiáñez
Mammalian sex is determined by opposing networks of ovarian and testicular genes that are well characterized; however, its epigenetic regulation is still largely unknown. Here we explore the 3D chromatin landscape of sex determination in vivo by profiling fluorescence-activated cell-sorted embryonic mouse gonadal populations in both sexes before and after sex determination. Through conventional Hi-C analyses, we show that chromatin structures, particularly topologically associating domains, remain largely unchanged during sex determination, suggesting a preformed configuration. We further integrate Hi-C data with ChIP-seq experiments using METALoci, a spatial autocorrelation analysis that identifies three-dimensional (3D) regulatory hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the 3D regulatory hubs of hundreds of genes that display time-specific and sex-specific expression. By combining predictive approaches and validations in transgenic mice, we identify a 3D regulatory hub for the protesticular gene Fgf9 . The deletion of this gonad-specific hub allows mutant mice to survive through development, overcoming lung lethality associated with Fgf9 loss of function while exhibiting male-to-female sex reversal. Through the reconstruction of gene regulatory networks, we identify a function for Meis genes, which act redundantly to specify sexual identity during ovarian and testicular development. Our results underscore the dynamic role of the 3D genome during sex determination, highlighting the potential of epigenomic approaches to uncover regulators of developmental processes.
{"title":"Chromatin spatial analysis by METALoci unveils sex-determining 3D regulatory hubs","authors":"Irene Mota-Gómez, Juan Antonio Rodríguez, Shannon Dupont, Alicia Hurtado, Vanessa Cadenas, Leo Zuber, Iago Maceda, Oscar Lao, Johanna Jedamzick, Ralf Kühn, Scott Lacadie, Sara Alexandra García-Moreno, Miguel Torres, Francisca M. Real, Rafael D. Acemel, Blanche Capel, Marc A. Marti-Renom, Darío G. Lupiáñez","doi":"10.1038/s41594-026-01749-z","DOIUrl":"https://doi.org/10.1038/s41594-026-01749-z","url":null,"abstract":"Mammalian sex is determined by opposing networks of ovarian and testicular genes that are well characterized; however, its epigenetic regulation is still largely unknown. Here we explore the 3D chromatin landscape of sex determination in vivo by profiling fluorescence-activated cell-sorted embryonic mouse gonadal populations in both sexes before and after sex determination. Through conventional Hi-C analyses, we show that chromatin structures, particularly topologically associating domains, remain largely unchanged during sex determination, suggesting a preformed configuration. We further integrate Hi-C data with ChIP-seq experiments using METALoci, a spatial autocorrelation analysis that identifies three-dimensional (3D) regulatory hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the 3D regulatory hubs of hundreds of genes that display time-specific and sex-specific expression. By combining predictive approaches and validations in transgenic mice, we identify a 3D regulatory hub for the protesticular gene <jats:italic>Fgf9</jats:italic> . The deletion of this gonad-specific hub allows mutant mice to survive through development, overcoming lung lethality associated with <jats:italic>Fgf9</jats:italic> loss of function while exhibiting male-to-female sex reversal. Through the reconstruction of gene regulatory networks, we identify a function for <jats:italic>Meis</jats:italic> genes, which act redundantly to specify sexual identity during ovarian and testicular development. Our results underscore the dynamic role of the 3D genome during sex determination, highlighting the potential of epigenomic approaches to uncover regulators of developmental processes.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-20DOI: 10.1038/s41594-026-01747-1
Tien-Chi Huang, Maria Rigau, Valeriya Malysheva, Chad Whilding, Stella Siciliani, Jingyu Li, Irina Balaguer Balsells, Pavel Artemov, Camille Dion, Mikhail Spivakov, Juan M. Vaquerizas, Petra Hajkova
Global epigenetic resetting in the gonadal primordial germ cells (PGCs) enables transition from early PGCs to gametogenesis and eventual restoring of totipotency after fertilization. This reprogramming process involves global DNA demethylation, changes in nuclear morphology and remodeling of repressive histone modifications. Here, using combined cytological and Hi-C-based methods, we reveal that, following the epigenetic reprogramming and concomitant with their commitment to gametogenesis, premeiotic gonadal germ cells display a distinct chromosome and genome architecture. This involves separation of individual chromosomes, anchoring of centromeres at the nuclear periphery, reduction in interchromosome interactions and disentangling of chromosome ends. Furthermore, genome-wide contact mapping documents remodeling of the three-dimensional (3D) genome architecture across all observable levels, including disruption of topologically associating domains (TADs), loss of detectable loops and reduced active–active compartment interactions. We further show that the diminished TADs correlate with the reduced levels of CCCTC-binding factor, thus providing an in vivo physiological model to understand genome folding principles. Lastly, we show that PGC-like cells, derived from embryonic stem cells, do not exhibit the same chromatin organization as embryonic germ cells. Collectively, our findings uncover the existence of a distinct chromatin architecture in premeiotic male and female gonadal germ cells and show that, alongside global DNA demethylation, the germline epigenetic reprogramming involves erasure of memory at the genome architectural level through profound reorganization of the 3D genome.
{"title":"Global reorganization of genome architecture at the transition to gametogenesis","authors":"Tien-Chi Huang, Maria Rigau, Valeriya Malysheva, Chad Whilding, Stella Siciliani, Jingyu Li, Irina Balaguer Balsells, Pavel Artemov, Camille Dion, Mikhail Spivakov, Juan M. Vaquerizas, Petra Hajkova","doi":"10.1038/s41594-026-01747-1","DOIUrl":"https://doi.org/10.1038/s41594-026-01747-1","url":null,"abstract":"Global epigenetic resetting in the gonadal primordial germ cells (PGCs) enables transition from early PGCs to gametogenesis and eventual restoring of totipotency after fertilization. This reprogramming process involves global DNA demethylation, changes in nuclear morphology and remodeling of repressive histone modifications. Here, using combined cytological and Hi-C-based methods, we reveal that, following the epigenetic reprogramming and concomitant with their commitment to gametogenesis, premeiotic gonadal germ cells display a distinct chromosome and genome architecture. This involves separation of individual chromosomes, anchoring of centromeres at the nuclear periphery, reduction in interchromosome interactions and disentangling of chromosome ends. Furthermore, genome-wide contact mapping documents remodeling of the three-dimensional (3D) genome architecture across all observable levels, including disruption of topologically associating domains (TADs), loss of detectable loops and reduced active–active compartment interactions. We further show that the diminished TADs correlate with the reduced levels of CCCTC-binding factor, thus providing an in vivo physiological model to understand genome folding principles. Lastly, we show that PGC-like cells, derived from embryonic stem cells, do not exhibit the same chromatin organization as embryonic germ cells. Collectively, our findings uncover the existence of a distinct chromatin architecture in premeiotic male and female gonadal germ cells and show that, alongside global DNA demethylation, the germline epigenetic reprogramming involves erasure of memory at the genome architectural level through profound reorganization of the 3D genome.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"174 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146223279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s41594-025-01742-y
Daniel Scholl, Tumara Boyd, Andrew P. Latham, Alexandra Salazar, Asma M. A. M. Khan, Steven Boeynaems, Alex S. Holehouse, Gabriel C. Lander, Andrej Sali, Donghyun Park, Ashok A. Deniz, Keren Lasker
Biomolecular condensates have key roles in regulating cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ). Here, we revealed hierarchical assembly of PopZ into a filamentous condensate by integrating cryo-electron tomography, biochemistry, single-molecule techniques and molecular dynamics simulations. The PopZ helical domain drives filamentation and condensation, while the disordered region inhibits them. Phase-dependent conformational changes prevent interfilament contacts in the dilute phase and expose client-binding sites in the dense phase. Perturbing filament formation in vitro alters the dynamics of scaffold and client proteins and the condensate’s wetting behavior. In cells, perturbing either filament formation or the ability of filaments to condense impairs PopZ function and leads to growth phenotypes. These findings establish a multiscale framework linking molecular interactions and condensate ultrastructure to cellular function.
{"title":"The filamentous ultrastructure of the PopZ condensate is required for its cellular function","authors":"Daniel Scholl, Tumara Boyd, Andrew P. Latham, Alexandra Salazar, Asma M. A. M. Khan, Steven Boeynaems, Alex S. Holehouse, Gabriel C. Lander, Andrej Sali, Donghyun Park, Ashok A. Deniz, Keren Lasker","doi":"10.1038/s41594-025-01742-y","DOIUrl":"https://doi.org/10.1038/s41594-025-01742-y","url":null,"abstract":"Biomolecular condensates have key roles in regulating cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ). Here, we revealed hierarchical assembly of PopZ into a filamentous condensate by integrating cryo-electron tomography, biochemistry, single-molecule techniques and molecular dynamics simulations. The PopZ helical domain drives filamentation and condensation, while the disordered region inhibits them. Phase-dependent conformational changes prevent interfilament contacts in the dilute phase and expose client-binding sites in the dense phase. Perturbing filament formation in vitro alters the dynamics of scaffold and client proteins and the condensate’s wetting behavior. In cells, perturbing either filament formation or the ability of filaments to condense impairs PopZ function and leads to growth phenotypes. These findings establish a multiscale framework linking molecular interactions and condensate ultrastructure to cellular function.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1038/s41594-025-01738-8
Stefano Annunziato,Chao Quan,Etienne J Donckele,Ilaria Lamberto,Richard D Bunker,Mary Zlotosch,Laura Schwander,Anastasia Murthy,Lars Wiedmer,Camille Staehly,Michelle Matysik,Samuel Gilberto,Despina Kapsitidou,Daric Wible,Gian Marco De Donatis,Peter Trenh,Rohitha SriRamaratnam,Vaik Strande,Raphael Lieberherr,David Lyon,Danielle Steiner,Joao Silva,Reinaldo Almeida,Elena Dolgikh,Bradley DeMarco,Jennifer Tsai,Amine Sadok,Vladislav Zarayskiy,Magnus Walter,Ralph Tiedt,Kevin J Lumb,Debora Bonenfant,Bernhard Fasching,John C Castle,Sharon A Townson,Pablo Gainza,Georg Petzold
Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4-RING E3 ubiquitin ligase (CRL4CRBN), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras-GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein-protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, 'glueprints') could become a viable strategy for the rational expansion of the MGD target repertoire.
{"title":"Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry.","authors":"Stefano Annunziato,Chao Quan,Etienne J Donckele,Ilaria Lamberto,Richard D Bunker,Mary Zlotosch,Laura Schwander,Anastasia Murthy,Lars Wiedmer,Camille Staehly,Michelle Matysik,Samuel Gilberto,Despina Kapsitidou,Daric Wible,Gian Marco De Donatis,Peter Trenh,Rohitha SriRamaratnam,Vaik Strande,Raphael Lieberherr,David Lyon,Danielle Steiner,Joao Silva,Reinaldo Almeida,Elena Dolgikh,Bradley DeMarco,Jennifer Tsai,Amine Sadok,Vladislav Zarayskiy,Magnus Walter,Ralph Tiedt,Kevin J Lumb,Debora Bonenfant,Bernhard Fasching,John C Castle,Sharon A Townson,Pablo Gainza,Georg Petzold","doi":"10.1038/s41594-025-01738-8","DOIUrl":"https://doi.org/10.1038/s41594-025-01738-8","url":null,"abstract":"Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4-RING E3 ubiquitin ligase (CRL4CRBN), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras-GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein-protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, 'glueprints') could become a viable strategy for the rational expansion of the MGD target repertoire.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"77 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：