Pub Date : 2025-01-02DOI: 10.1038/s41594-024-01424-1
A genetic variant specific to people of African ancestry increases the risk of neurodegenerative diseases, such as Parkinson disease (PD). This variant occurs in a noncoding region and interferes with the splicing of mRNA transcripts, resulting in lowered protein levels and activity. This work reveals a novel therapeutic target in an underserved and underrepresented population.
{"title":"Intronic variant increases Parkinson disease risk by disrupting branchpoint sequence","authors":"","doi":"10.1038/s41594-024-01424-1","DOIUrl":"10.1038/s41594-024-01424-1","url":null,"abstract":"A genetic variant specific to people of African ancestry increases the risk of neurodegenerative diseases, such as Parkinson disease (PD). This variant occurs in a noncoding region and interferes with the splicing of mRNA transcripts, resulting in lowered protein levels and activity. This work reveals a novel therapeutic target in an underserved and underrepresented population.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"12-13"},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911432","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 : 2024-12-31DOI: 10.1038/s41594-024-01461-w
Grace Hohman, Michael Shahid, Mohamed Eldeeb
Targeted protein degradation is a promising drug discovery approach. A study now describes transferrin receptor targeting chimeras (TransTACS), which lysosomally degrade membrane proteins with potent specificity and efficacy. TransTACs reversibly regulate the tumor-killing activity of CAR-T cells and inhibit drug-resistant EGFR-driven cancers in mice.
{"title":"Targeted degradation of membrane proteins","authors":"Grace Hohman, Michael Shahid, Mohamed Eldeeb","doi":"10.1038/s41594-024-01461-w","DOIUrl":"10.1038/s41594-024-01461-w","url":null,"abstract":"Targeted protein degradation is a promising drug discovery approach. A study now describes transferrin receptor targeting chimeras (TransTACS), which lysosomally degrade membrane proteins with potent specificity and efficacy. TransTACs reversibly regulate the tumor-killing activity of CAR-T cells and inhibit drug-resistant EGFR-driven cancers in mice.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"2-4"},"PeriodicalIF":12.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905035","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 : 2024-12-30DOI: 10.1038/s41594-024-01460-x
Daniel P. Bondeson
XPR1 is the only annotated phosphate exporter protein in humans. Recent studies provide mechanistic clues to its cellular function; three posit non-export mechanisms to regulate phosphate homeostasis, while six present high-resolution cryo-EM data supporting a bona fide phosphate channel mechanism controlled by intracellular phosphate levels.
{"title":"Insights into phosphate homeostasis regulation by XPR1","authors":"Daniel P. Bondeson","doi":"10.1038/s41594-024-01460-x","DOIUrl":"10.1038/s41594-024-01460-x","url":null,"abstract":"XPR1 is the only annotated phosphate exporter protein in humans. Recent studies provide mechanistic clues to its cellular function; three posit non-export mechanisms to regulate phosphate homeostasis, while six present high-resolution cryo-EM data supporting a bona fide phosphate channel mechanism controlled by intracellular phosphate levels.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"5-7"},"PeriodicalIF":12.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901591","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 : 2024-12-27DOI: 10.1038/s41594-024-01440-1
Regina Mencia, Agustín L. Arce, Candela Houriet, Wenfei Xian, Adrián Contreras, Gautam Shirsekar, Detlef Weigel, Pablo A. Manavella
Infectious diseases drive wild plant evolution and impact crop yield. Plants, like animals, sense biotic threats through pattern recognition receptors (PRRs). Overly robust immune responses can harm plants; thus, understanding the tuning of defense response mechanisms is crucial for developing pathogen-resistant crops. In this study, we found that an inverted-repeat transposon (EFR-associated IR, Ea-IR) located between the loci encoding PRRs ELONGATION FACTOR-TU RECEPTOR (EFR) and myosin XI-k (XI-k) in Arabidopsis affects chromatin organization, promoting the formation of a repressive chromatin loop. Upon pathogen infection, chromatin changes around EFR and XI-k correlate with increased EFR transcription. Pathogen-induced chromatin opening causes RNA polymerase II readthrough, producing a longer, Ea-IR-containing XI-k transcript, processed by Dicer-like enzymes into small RNAs, which reset chromatin to a repressive state attenuating the immune response after infection. Arabidopsis accessions lacking Ea-IR have higher basal EFR levels and resistance to pathogens. We show a scenario in which a transposon, chromatin organization and gene expression interact to fine-tune immune responses, during both the course of infection and the course of evolution. Here, the authors show that an inverted-repeat transposon located next to the pattern recognition receptor ELONGATION FACTOR-TU RECEPTOR (EFR)-encoding gene in Arabidopsis controls chromatin organization, EFR gene expression and plant immune response.
传染病推动野生植物进化，影响作物产量。植物和动物一样，通过模式识别受体（PRRs）感知生物威胁。过度强烈的免疫反应会伤害植物；因此，了解防御反应机制的调整对开发抗病作物至关重要。在本研究中，我们发现拟南芥中位于编码PRRs的伸长因子- tu受体（EFR）和肌球蛋白XI-k （XI-k）位点之间的倒置重复转座子（EFR-associated IR, Ea-IR）影响染色质组织，促进抑制染色质环的形成。在病原体感染后，EFR和XI-k周围的染色质变化与EFR转录增加相关。病原体诱导的染色质打开导致RNA聚合酶II读取，产生更长的含有ea - ir的XI-k转录物，由dicer样酶加工成小RNA，将染色质复位到抑制状态，从而减弱感染后的免疫反应。缺乏Ea-IR的拟南芥材料具有较高的基础EFR水平和对病原体的抗性。我们展示了转座子、染色质组织和基因表达在感染和进化过程中相互作用以微调免疫反应的场景。
{"title":"Transposon-triggered epigenetic chromatin dynamics modulate EFR-related pathogen response","authors":"Regina Mencia, Agustín L. Arce, Candela Houriet, Wenfei Xian, Adrián Contreras, Gautam Shirsekar, Detlef Weigel, Pablo A. Manavella","doi":"10.1038/s41594-024-01440-1","DOIUrl":"10.1038/s41594-024-01440-1","url":null,"abstract":"Infectious diseases drive wild plant evolution and impact crop yield. Plants, like animals, sense biotic threats through pattern recognition receptors (PRRs). Overly robust immune responses can harm plants; thus, understanding the tuning of defense response mechanisms is crucial for developing pathogen-resistant crops. In this study, we found that an inverted-repeat transposon (EFR-associated IR, Ea-IR) located between the loci encoding PRRs ELONGATION FACTOR-TU RECEPTOR (EFR) and myosin XI-k (XI-k) in Arabidopsis affects chromatin organization, promoting the formation of a repressive chromatin loop. Upon pathogen infection, chromatin changes around EFR and XI-k correlate with increased EFR transcription. Pathogen-induced chromatin opening causes RNA polymerase II readthrough, producing a longer, Ea-IR-containing XI-k transcript, processed by Dicer-like enzymes into small RNAs, which reset chromatin to a repressive state attenuating the immune response after infection. Arabidopsis accessions lacking Ea-IR have higher basal EFR levels and resistance to pathogens. We show a scenario in which a transposon, chromatin organization and gene expression interact to fine-tune immune responses, during both the course of infection and the course of evolution. Here, the authors show that an inverted-repeat transposon located next to the pattern recognition receptor ELONGATION FACTOR-TU RECEPTOR (EFR)-encoding gene in Arabidopsis controls chromatin organization, EFR gene expression and plant immune response.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"199-211"},"PeriodicalIF":12.5,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01440-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887510","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 : 2024-12-12DOI: 10.1038/s41594-024-01423-2
Pilar Álvarez Jerez, Peter Wild Crea, Daniel M. Ramos, Emil K. Gustavsson, Mandy Radefeldt, Andrey Damianov, Mary B. Makarious, Oluwadamilola O. Ojo, Kimberley J. Billingsley, Laksh Malik, Kensuke Daida, Sarah Bromberek, Fangle Hu, Zachary Schneider, Aditya L. Surapaneni, Julia Stadler, Mie Rizig, Huw R. Morris, Caroline B. Pantazis, Hampton L. Leonard, Laurel Screven, Yue A. Qi, Mike A. Nalls, Sara Bandres-Ciga, John Hardy, Henry Houlden, Celeste Eng, Esteban González Burchard, Linda Kachuri, Chia-Ho Lin, Douglas L. Black, Global Parkinson’s Genetics Program (GP2), Andrew B. Singleton, Steffen Fischer, Peter Bauer, Xylena Reed, Mina Ryten, Christian Beetz, Michael Ward, Njideka U. Okubadejo, Cornelis Blauwendraat
Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population. Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.
{"title":"African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1","authors":"Pilar Álvarez Jerez, Peter Wild Crea, Daniel M. Ramos, Emil K. Gustavsson, Mandy Radefeldt, Andrey Damianov, Mary B. Makarious, Oluwadamilola O. Ojo, Kimberley J. Billingsley, Laksh Malik, Kensuke Daida, Sarah Bromberek, Fangle Hu, Zachary Schneider, Aditya L. Surapaneni, Julia Stadler, Mie Rizig, Huw R. Morris, Caroline B. Pantazis, Hampton L. Leonard, Laurel Screven, Yue A. Qi, Mike A. Nalls, Sara Bandres-Ciga, John Hardy, Henry Houlden, Celeste Eng, Esteban González Burchard, Linda Kachuri, Chia-Ho Lin, Douglas L. Black, Global Parkinson’s Genetics Program (GP2), Andrew B. Singleton, Steffen Fischer, Peter Bauer, Xylena Reed, Mina Ryten, Christian Beetz, Michael Ward, Njideka U. Okubadejo, Cornelis Blauwendraat","doi":"10.1038/s41594-024-01423-2","DOIUrl":"10.1038/s41594-024-01423-2","url":null,"abstract":"Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population. Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1955-1963"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01423-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811350","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 : 2024-12-12DOI: 10.1038/s41594-024-01459-4
As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.
随着2024年的结束，我们借此机会反思我们30周年的亮点，并考虑该领域的未来。
{"title":"30 years of structural and molecular biology and counting","authors":"","doi":"10.1038/s41594-024-01459-4","DOIUrl":"10.1038/s41594-024-01459-4","url":null,"abstract":"As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1811-1811"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01459-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811391","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 : 2024-12-04DOI: 10.1038/s41594-024-01422-3
Mateusz C. Ambrozkiewicz, Sonja Lorenz
Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications. In this perspective, the authors showcase the importance and need for additional investigation of the ubiquitin-dependent regulation of neurodevelopment. They then propose interdisciplinary approaches that will allow improved spatiotemporal understanding of this relationship in the context of basic neuroscience and disease.
{"title":"Understanding ubiquitination in neurodevelopment by integrating insights across space and time","authors":"Mateusz C. Ambrozkiewicz, Sonja Lorenz","doi":"10.1038/s41594-024-01422-3","DOIUrl":"10.1038/s41594-024-01422-3","url":null,"abstract":"Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications. In this perspective, the authors showcase the importance and need for additional investigation of the ubiquitin-dependent regulation of neurodevelopment. They then propose interdisciplinary approaches that will allow improved spatiotemporal understanding of this relationship in the context of basic neuroscience and disease.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 1","pages":"14-22"},"PeriodicalIF":12.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763462","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 : 2024-11-29DOI: 10.1038/s41594-024-01438-9
Emmanuel Nji, Aurélien F. A. Moumbock, Katharina C. Cramer, Nicolas V. Rüffin, Jamaine Davis, Oluwatoyin A. Asojo, Julia J. Griese, Amma A. Larbi, Michel N. Fodje
{"title":"Supporting structural biologists in Africa requires resources and capacity building","authors":"Emmanuel Nji, Aurélien F. A. Moumbock, Katharina C. Cramer, Nicolas V. Rüffin, Jamaine Davis, Oluwatoyin A. Asojo, Julia J. Griese, Amma A. Larbi, Michel N. Fodje","doi":"10.1038/s41594-024-01438-9","DOIUrl":"10.1038/s41594-024-01438-9","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1814-1815"},"PeriodicalIF":12.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753750","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 : 2024-11-28DOI: 10.1038/s41594-024-01436-x
Christian Cambillau
{"title":"Looking back at the timely launch of Nature Structural Biology in 1994","authors":"Christian Cambillau","doi":"10.1038/s41594-024-01436-x","DOIUrl":"10.1038/s41594-024-01436-x","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1812-1812"},"PeriodicalIF":12.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751089","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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