Pub Date : 2024-06-25DOI: 10.1038/s41594-024-01343-1
Overexpression of the RNA methyltransferase METTL6 leads to increased proliferation and promotes cancer. Our cryo-electron microscopy (cryo-EM) and biochemical analyses reveal that METTL6 requires seryl-tRNA synthetase as a cofactor to efficiently generate 3-methyl-cytosine in serine tRNAs.
{"title":"The tRNA methyltransferase METTL6 requires seryl-tRNA synthetase for tRNASer targeting","authors":"","doi":"10.1038/s41594-024-01343-1","DOIUrl":"10.1038/s41594-024-01343-1","url":null,"abstract":"Overexpression of the RNA methyltransferase METTL6 leads to increased proliferation and promotes cancer. Our cryo-electron microscopy (cryo-EM) and biochemical analyses reveal that METTL6 requires seryl-tRNA synthetase as a cofactor to efficiently generate 3-methyl-cytosine in serine tRNAs.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1464-1465"},"PeriodicalIF":12.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448111","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 : 2024-06-25DOI: 10.1038/s41594-024-01338-y
Elias Adriaenssens, Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Martina Schuschnig, Stephen Shoebridge, Marvin Skulsuppaisarn, Emily Maria Watts, Kitti Dora Csalyi, Benjamin Scott Padman, Michael Lazarou, Sascha Martens
Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression. Mitophagy is an important quality control pathway. Here, the authors identify the mechanisms enabling the TBK1 adaptors NAP1 and SINTBAD to prevent hyperactivation of PINK1/Parkin mitophagy while promoting the pathway once set in motion.
{"title":"Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD","authors":"Elias Adriaenssens, Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Martina Schuschnig, Stephen Shoebridge, Marvin Skulsuppaisarn, Emily Maria Watts, Kitti Dora Csalyi, Benjamin Scott Padman, Michael Lazarou, Sascha Martens","doi":"10.1038/s41594-024-01338-y","DOIUrl":"10.1038/s41594-024-01338-y","url":null,"abstract":"Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression. Mitophagy is an important quality control pathway. Here, the authors identify the mechanisms enabling the TBK1 adaptors NAP1 and SINTBAD to prevent hyperactivation of PINK1/Parkin mitophagy while promoting the pathway once set in motion.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1717-1731"},"PeriodicalIF":12.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01338-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448223","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 : 2024-06-25DOI: 10.1038/s41594-024-01342-2
Huasong Ai, Zaozhen He, Zhiheng Deng, Guo-Chao Chu, Qiang Shi, Zebin Tong, Jia-Bin Li, Man Pan, Lei Liu
Epigenetic regulators have a crucial effect on gene expression based on their manipulation of histone modifications. Histone H2AK119 monoubiquitination (H2AK119Ub), a well-established hallmark in transcription repression, is dynamically regulated by the opposing activities of Polycomb repressive complex 1 (PRC1) and nucleosome deubiquitinases including the primary human USP16 and Polycomb repressive deubiquitinase (PR-DUB) complex. Recently, the catalytic mechanism for the multi-subunit PR-DUB complex has been described, but how the single-subunit USP16 recognizes the H2AK119Ub nucleosome and cleaves the ubiquitin (Ub) remains unknown. Here we report the cryo-EM structure of USP16–H2AK119Ub nucleosome complex, which unveils a fundamentally distinct mode of H2AK119Ub deubiquitination compared to PR-DUB, encompassing the nucleosome recognition pattern independent of the H2A–H2B acidic patch and the conformational heterogeneity in the Ub motif and the histone H2A C-terminal tail. Our work highlights the mechanism diversity of H2AK119Ub deubiquitination and provides a structural framework for understanding the disease-causing mutations of USP16. The H2AK119Ub is inversely regulated by nucleosomal deubiquitinase. Here the authors report the cryo-EM structure of single-subunit USP16 bound to H2AK119Ub nucleosome, unveiling a fundamentally distinct mode of H2AK119Ub deubiquitination compared to multi-subunit PR-DUB.
{"title":"Structural and mechanistic basis for nucleosomal H2AK119 deubiquitination by single-subunit deubiquitinase USP16","authors":"Huasong Ai, Zaozhen He, Zhiheng Deng, Guo-Chao Chu, Qiang Shi, Zebin Tong, Jia-Bin Li, Man Pan, Lei Liu","doi":"10.1038/s41594-024-01342-2","DOIUrl":"10.1038/s41594-024-01342-2","url":null,"abstract":"Epigenetic regulators have a crucial effect on gene expression based on their manipulation of histone modifications. Histone H2AK119 monoubiquitination (H2AK119Ub), a well-established hallmark in transcription repression, is dynamically regulated by the opposing activities of Polycomb repressive complex 1 (PRC1) and nucleosome deubiquitinases including the primary human USP16 and Polycomb repressive deubiquitinase (PR-DUB) complex. Recently, the catalytic mechanism for the multi-subunit PR-DUB complex has been described, but how the single-subunit USP16 recognizes the H2AK119Ub nucleosome and cleaves the ubiquitin (Ub) remains unknown. Here we report the cryo-EM structure of USP16–H2AK119Ub nucleosome complex, which unveils a fundamentally distinct mode of H2AK119Ub deubiquitination compared to PR-DUB, encompassing the nucleosome recognition pattern independent of the H2A–H2B acidic patch and the conformational heterogeneity in the Ub motif and the histone H2A C-terminal tail. Our work highlights the mechanism diversity of H2AK119Ub deubiquitination and provides a structural framework for understanding the disease-causing mutations of USP16. The H2AK119Ub is inversely regulated by nucleosomal deubiquitinase. Here the authors report the cryo-EM structure of single-subunit USP16 bound to H2AK119Ub nucleosome, unveiling a fundamentally distinct mode of H2AK119Ub deubiquitination compared to multi-subunit PR-DUB.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1745-1755"},"PeriodicalIF":12.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448217","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 : 2024-06-19DOI: 10.1038/s41594-024-01339-x
Duc-Duy Vu, Alessio Bonucci, Manon Brenière, Metztli Cisneros-Aguirre, Philippe Pelupessy, Ziqing Wang, Ludovic Carlier, Guillaume Bouvignies, Patricia Cortes, Aneel K. Aggarwal, Martin Blackledge, Zoher Gueroui, Valérie Belle, Jeremy M. Stark, Mauro Modesti, Fabien Ferrage
In mammalian cells, DNA double-strand breaks are predominantly repaired by non-homologous end joining (NHEJ). During repair, the Ku70–Ku80 heterodimer (Ku), X-ray repair cross complementing 4 (XRCC4) in complex with DNA ligase 4 (X4L4) and XRCC4-like factor (XLF) form a flexible scaffold that holds the broken DNA ends together. Insights into the architectural organization of the NHEJ scaffold and its regulation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) were recently obtained by single-particle cryo-electron microscopy analysis. However, several regions, especially the C-terminal regions (CTRs) of the XRCC4 and XLF scaffolding proteins, have largely remained unresolved in experimental structures, which hampers the understanding of their functions. Here we used magnetic resonance techniques and biochemical assays to comprehensively characterize the interactions and dynamics of the XRCC4 and XLF CTRs at residue resolution. We show that the CTRs of XRCC4 and XLF are intrinsically disordered and form a network of multivalent heterotypic and homotypic interactions that promotes robust cellular NHEJ activity. Importantly, we demonstrate that the multivalent interactions of these CTRs lead to the formation of XLF and X4L4 condensates in vitro, which can recruit relevant effectors and critically stimulate DNA end ligation. Our work highlights the role of disordered regions in the mechanism and dynamics of NHEJ and lays the groundwork for the investigation of NHEJ protein disorder and its associated condensates inside cells with implications in cancer biology, immunology and the development of genome-editing strategies. What is the role of disorder in non-homologous end-joining proteins? The authors use nuclear magnetic resonance to reveal that disordered regions mediate a network of multivalent interactions, promoting biomolecular condensation that accelerates DNA ligation kinetics.
{"title":"Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro","authors":"Duc-Duy Vu, Alessio Bonucci, Manon Brenière, Metztli Cisneros-Aguirre, Philippe Pelupessy, Ziqing Wang, Ludovic Carlier, Guillaume Bouvignies, Patricia Cortes, Aneel K. Aggarwal, Martin Blackledge, Zoher Gueroui, Valérie Belle, Jeremy M. Stark, Mauro Modesti, Fabien Ferrage","doi":"10.1038/s41594-024-01339-x","DOIUrl":"10.1038/s41594-024-01339-x","url":null,"abstract":"In mammalian cells, DNA double-strand breaks are predominantly repaired by non-homologous end joining (NHEJ). During repair, the Ku70–Ku80 heterodimer (Ku), X-ray repair cross complementing 4 (XRCC4) in complex with DNA ligase 4 (X4L4) and XRCC4-like factor (XLF) form a flexible scaffold that holds the broken DNA ends together. Insights into the architectural organization of the NHEJ scaffold and its regulation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) were recently obtained by single-particle cryo-electron microscopy analysis. However, several regions, especially the C-terminal regions (CTRs) of the XRCC4 and XLF scaffolding proteins, have largely remained unresolved in experimental structures, which hampers the understanding of their functions. Here we used magnetic resonance techniques and biochemical assays to comprehensively characterize the interactions and dynamics of the XRCC4 and XLF CTRs at residue resolution. We show that the CTRs of XRCC4 and XLF are intrinsically disordered and form a network of multivalent heterotypic and homotypic interactions that promotes robust cellular NHEJ activity. Importantly, we demonstrate that the multivalent interactions of these CTRs lead to the formation of XLF and X4L4 condensates in vitro, which can recruit relevant effectors and critically stimulate DNA end ligation. Our work highlights the role of disordered regions in the mechanism and dynamics of NHEJ and lays the groundwork for the investigation of NHEJ protein disorder and its associated condensates inside cells with implications in cancer biology, immunology and the development of genome-editing strategies. What is the role of disorder in non-homologous end-joining proteins? The authors use nuclear magnetic resonance to reveal that disordered regions mediate a network of multivalent interactions, promoting biomolecular condensation that accelerates DNA ligation kinetics.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1732-1744"},"PeriodicalIF":12.5,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425193","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 : 2024-06-18DOI: 10.1038/s41594-024-01331-5
Fasséli Coulibaly
Poxviruses range from deadly smallpox to attenuated vaccinia virus used in vaccines and oncolytic vectors. Despite their broad, if antithetical, effects on humankind, the mechanistic details of poxvirus assembly are not known. Here we discuss advances in revealing the structure of the palisade layer which underlies the viral core morphology.
{"title":"Structure of the poxvirus core","authors":"Fasséli Coulibaly","doi":"10.1038/s41594-024-01331-5","DOIUrl":"10.1038/s41594-024-01331-5","url":null,"abstract":"Poxviruses range from deadly smallpox to attenuated vaccinia virus used in vaccines and oncolytic vectors. Despite their broad, if antithetical, effects on humankind, the mechanistic details of poxvirus assembly are not known. Here we discuss advances in revealing the structure of the palisade layer which underlies the viral core morphology.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 7","pages":"1001-1003"},"PeriodicalIF":12.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334405","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 : 2024-06-18DOI: 10.1038/s41594-024-01319-1
Qian Li, Jun Zhang, Cory Haluska, Xiang Zhang, Lei Wang, Guangfeng Liu, Zhaoning Wang, Duo Jin, Tong Cheng, Hongxia Wang, Yuan Tian, Xiangxi Wang, Lei Sun, Xiaolan Zhao, Zhenguo Chen, Lanfeng Wang
Smc5/6 is a member of the eukaryotic structural maintenance of chromosomes (SMC) family of complexes with important roles in genome maintenance and viral restriction. However, limited structural understanding of Smc5/6 hinders the elucidation of its diverse functions. Here, we report cryo-EM structures of the budding yeast Smc5/6 complex in eight-subunit, six-subunit and five-subunit states. Structural maps throughout the entire length of these complexes reveal modularity and key elements in complex assembly. We show that the non-SMC element (Nse)2 subunit supports the overall shape of the complex and uses a wedge motif to aid the stability and function of the complex. The Nse6 subunit features a flexible hook region for attachment to the Smc5 and Smc6 arm regions, contributing to the DNA repair roles of the complex. Our results also suggest a structural basis for the opposite effects of the Nse1–3–4 and Nse5–6 subcomplexes in regulating Smc5/6 ATPase activity. Collectively, our integrated structural and functional data provide a framework for understanding Smc5/6 assembly and function. Cryo-EM structures covering full-length yeast Smc5/6 in three states and the accompanying mutagenesis data reveal multiple new structural and functional features of this unique SMC complex.
{"title":"Cryo-EM structures of Smc5/6 in multiple states reveal its assembly and functional mechanisms","authors":"Qian Li, Jun Zhang, Cory Haluska, Xiang Zhang, Lei Wang, Guangfeng Liu, Zhaoning Wang, Duo Jin, Tong Cheng, Hongxia Wang, Yuan Tian, Xiangxi Wang, Lei Sun, Xiaolan Zhao, Zhenguo Chen, Lanfeng Wang","doi":"10.1038/s41594-024-01319-1","DOIUrl":"10.1038/s41594-024-01319-1","url":null,"abstract":"Smc5/6 is a member of the eukaryotic structural maintenance of chromosomes (SMC) family of complexes with important roles in genome maintenance and viral restriction. However, limited structural understanding of Smc5/6 hinders the elucidation of its diverse functions. Here, we report cryo-EM structures of the budding yeast Smc5/6 complex in eight-subunit, six-subunit and five-subunit states. Structural maps throughout the entire length of these complexes reveal modularity and key elements in complex assembly. We show that the non-SMC element (Nse)2 subunit supports the overall shape of the complex and uses a wedge motif to aid the stability and function of the complex. The Nse6 subunit features a flexible hook region for attachment to the Smc5 and Smc6 arm regions, contributing to the DNA repair roles of the complex. Our results also suggest a structural basis for the opposite effects of the Nse1–3–4 and Nse5–6 subcomplexes in regulating Smc5/6 ATPase activity. Collectively, our integrated structural and functional data provide a framework for understanding Smc5/6 assembly and function. Cryo-EM structures covering full-length yeast Smc5/6 in three states and the accompanying mutagenesis data reveal multiple new structural and functional features of this unique SMC complex.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1532-1542"},"PeriodicalIF":12.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334155","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 : 2024-06-18DOI: 10.1038/s41594-024-01337-z
Xiaozhan Qu, Shuo Zhao, Chanjuan Wan, Lei Zhu, Tuo Ji, Paolo Rossi, Junfeng Wang, Charalampos G. Kalodimos, Chao Wang, Weiya Xu, Chengdong Huang
Molecular chaperone heat shock protein 90 (Hsp90) is a ubiquitous regulator that fine-tunes and remodels diverse client proteins, exerting profound effects on normal biology and diseases. Unraveling the mechanistic details of Hsp90’s function requires atomic-level insights into its client interactions throughout the adenosine triphosphate-coupled functional cycle. However, the structural details of the initial encounter complex in the chaperone cycle, wherein Hsp90 adopts an open conformation while engaging with the client, remain elusive. Here, using nuclear magnetic resonance spectroscopy, we determined the solution structure of Hsp90 in its open state, bound to a disordered client. Our findings reveal that Hsp90 uses two distinct binding sites, collaborating synergistically to capture discrete hydrophobic segments within client proteins. This bipartite interaction generates a versatile complex that facilitates rapid conformational sampling. Moreover, our investigations spanning various clients and Hsp90 orthologs demonstrate a pervasive mechanism used by Hsp90 orthologs to accommodate the vast array of client proteins. Collectively, our work contributes to establish a unified conceptual and mechanistic framework, elucidating the intricate interplay between Hsp90 and its clients. Here, using nuclear magnetic resonance spectroscopy, the authors delineate how the molecular chaperone Hsp90, in its open state, uses its two middle domains to synergistically capture a disordered client in a highly dynamic manner, forming a bipartite complex.
{"title":"Structural basis for the dynamic chaperoning of disordered clients by Hsp90","authors":"Xiaozhan Qu, Shuo Zhao, Chanjuan Wan, Lei Zhu, Tuo Ji, Paolo Rossi, Junfeng Wang, Charalampos G. Kalodimos, Chao Wang, Weiya Xu, Chengdong Huang","doi":"10.1038/s41594-024-01337-z","DOIUrl":"10.1038/s41594-024-01337-z","url":null,"abstract":"Molecular chaperone heat shock protein 90 (Hsp90) is a ubiquitous regulator that fine-tunes and remodels diverse client proteins, exerting profound effects on normal biology and diseases. Unraveling the mechanistic details of Hsp90’s function requires atomic-level insights into its client interactions throughout the adenosine triphosphate-coupled functional cycle. However, the structural details of the initial encounter complex in the chaperone cycle, wherein Hsp90 adopts an open conformation while engaging with the client, remain elusive. Here, using nuclear magnetic resonance spectroscopy, we determined the solution structure of Hsp90 in its open state, bound to a disordered client. Our findings reveal that Hsp90 uses two distinct binding sites, collaborating synergistically to capture discrete hydrophobic segments within client proteins. This bipartite interaction generates a versatile complex that facilitates rapid conformational sampling. Moreover, our investigations spanning various clients and Hsp90 orthologs demonstrate a pervasive mechanism used by Hsp90 orthologs to accommodate the vast array of client proteins. Collectively, our work contributes to establish a unified conceptual and mechanistic framework, elucidating the intricate interplay between Hsp90 and its clients. Here, using nuclear magnetic resonance spectroscopy, the authors delineate how the molecular chaperone Hsp90, in its open state, uses its two middle domains to synergistically capture a disordered client in a highly dynamic manner, forming a bipartite complex.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1482-1491"},"PeriodicalIF":12.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334417","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 : 2024-06-13DOI: 10.1038/s41594-024-01332-4
Feng Wang, Qing He, Nina Y. Yao, Michael E. O’Donnell, Huilin Li
Humans have three different proliferating cell nuclear antigen (PCNA) clamp-loading complexes: RFC and CTF18-RFC load PCNA onto DNA, but ATAD5-RFC can only unload PCNA from DNA. The underlying structural basis of ATAD5-RFC unloading is unknown. We show here that ATAD5 has two unique locking loops that appear to tie the complex into a rigid structure, and together with a domain that plugs the DNA-binding chamber, prevent conformation changes required for DNA binding, likely explaining why ATAD5-RFC is exclusively a PCNA unloader. These features are conserved in the yeast PCNA unloader Elg1-RFC. We observe intermediates in which PCNA bound to ATAD5-RFC exists as a closed planar ring, a cracked spiral or a gapped spiral. Surprisingly, ATAD5-RFC can open a PCNA gap between PCNA protomers 2 and 3, different from the PCNA protomers 1 and 3 gap observed in all previously characterized clamp loaders. Cryo-EM structures of the human clamp unloader ATAD5-RFC bound to the sliding clamp PCNA reveal two unique locking loops and one chamber plug that prevent DNA from entering the ATAD5-RFC and explain why ATAD5-RFC is exclusively a PCNA unloader.
{"title":"The human ATAD5 has evolved unique structural elements to function exclusively as a PCNA unloader","authors":"Feng Wang, Qing He, Nina Y. Yao, Michael E. O’Donnell, Huilin Li","doi":"10.1038/s41594-024-01332-4","DOIUrl":"10.1038/s41594-024-01332-4","url":null,"abstract":"Humans have three different proliferating cell nuclear antigen (PCNA) clamp-loading complexes: RFC and CTF18-RFC load PCNA onto DNA, but ATAD5-RFC can only unload PCNA from DNA. The underlying structural basis of ATAD5-RFC unloading is unknown. We show here that ATAD5 has two unique locking loops that appear to tie the complex into a rigid structure, and together with a domain that plugs the DNA-binding chamber, prevent conformation changes required for DNA binding, likely explaining why ATAD5-RFC is exclusively a PCNA unloader. These features are conserved in the yeast PCNA unloader Elg1-RFC. We observe intermediates in which PCNA bound to ATAD5-RFC exists as a closed planar ring, a cracked spiral or a gapped spiral. Surprisingly, ATAD5-RFC can open a PCNA gap between PCNA protomers 2 and 3, different from the PCNA protomers 1 and 3 gap observed in all previously characterized clamp loaders. Cryo-EM structures of the human clamp unloader ATAD5-RFC bound to the sliding clamp PCNA reveal two unique locking loops and one chamber plug that prevent DNA from entering the ATAD5-RFC and explain why ATAD5-RFC is exclusively a PCNA unloader.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1680-1691"},"PeriodicalIF":12.5,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01332-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315573","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 : 2024-06-12DOI: 10.1038/s41594-024-01330-6
An iron-induced ferroptosis screen revealed PRDX6 as a selenoprotein-synthesis factor. Loss of PRDX6 substantially decreased expression of the selenoprotein GPX4, a master regulator of ferroptosis, and induced ferroptosis. Mechanistically, PRDX6 increases the efficiency of selenium use by acting as a selenium delivery protein.
{"title":"Efficient selenium use by PRDX6 suppresses iron toxicity and ferroptosis","authors":"","doi":"10.1038/s41594-024-01330-6","DOIUrl":"10.1038/s41594-024-01330-6","url":null,"abstract":"An iron-induced ferroptosis screen revealed PRDX6 as a selenoprotein-synthesis factor. Loss of PRDX6 substantially decreased expression of the selenoprotein GPX4, a master regulator of ferroptosis, and induced ferroptosis. Mechanistically, PRDX6 increases the efficiency of selenium use by acting as a selenium delivery protein.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 8","pages":"1154-1155"},"PeriodicalIF":12.5,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309087","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}
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：