Nature Structural & Molecular Biology最新文献_第10页

Guiding the HBO1 complex function through the JADE subunit 通过 JADE 亚基引导 HBO1 复合物的功能。

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-03-06 DOI: 10.1038/s41594-024-01245-2

Nitika Gaurav, Akinori Kanai, Catherine Lachance, Khan L. Cox, Jiuyang Liu, Adrian T. Grzybowski, Nehmé Saksouk, Brianna J. Klein, Yosuke Komata, Shuhei Asada, Alexander J. Ruthenburg, Michael G. Poirier, Jacques Côté, Akihiko Yokoyama, Tatiana G. Kutateladze

{"title":"Guiding the HBO1 complex function through the JADE subunit","authors":"Nitika Gaurav, Akinori Kanai, Catherine Lachance, Khan L. Cox, Jiuyang Liu, Adrian T. Grzybowski, Nehmé Saksouk, Brianna J. Klein, Yosuke Komata, Shuhei Asada, Alexander J. Ruthenburg, Michael G. Poirier, Jacques Côté, Akihiko Yokoyama, Tatiana G. Kutateladze","doi":"10.1038/s41594-024-01245-2","DOIUrl":"10.1038/s41594-024-01245-2","url":null,"abstract":"JADE is a core subunit of the HBO1 acetyltransferase complex that regulates developmental and epigenetic programs and promotes gene transcription. Here we describe the mechanism by which JADE facilitates recruitment of the HBO1 complex to chromatin and mediates its enzymatic activity. Structural, genomic and complex assembly in vivo studies show that the PZP (PHD1–zinc-knuckle–PHD2) domain of JADE engages the nucleosome through binding to histone H3 and DNA and is necessary for the association with chromatin targets. Recognition of unmethylated H3K4 by PZP directs enzymatic activity of the complex toward histone H4 acetylation, whereas H3K4 hypermethylation alters histone substrate selectivity. We demonstrate that PZP contributes to leukemogenesis, augmenting transforming activity of the NUP98–JADE2 fusion. Our findings highlight biological consequences and the impact of the intact JADE subunit on genomic recruitment, enzymatic function and pathological activity of the HBO1 complex. JADE is a subunit of human acetyltransferase complex HBO1 that is essential in transcriptional regulation. Gaurav et al. characterize the molecular mechanism by which JADE mediates genomic association and enzymatic and pathological activities of the HBO1 complex.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049927","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}

引用次数: 0

Regulatory activity is the default DNA state in eukaryotes 调控活性是真核生物 DNA 的默认状态

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-03-06 DOI: 10.1038/s41594-024-01235-4

Ishika Luthra, Cassandra Jensen, Xinyi E. Chen, Asfar Lathif Salaudeen, Abdul Muntakim Rafi, Carl G. de Boer

{"title":"Regulatory activity is the default DNA state in eukaryotes","authors":"Ishika Luthra, Cassandra Jensen, Xinyi E. Chen, Asfar Lathif Salaudeen, Abdul Muntakim Rafi, Carl G. de Boer","doi":"10.1038/s41594-024-01235-4","DOIUrl":"10.1038/s41594-024-01235-4","url":null,"abstract":"Genomes encode for genes and non-coding DNA, both capable of transcriptional activity. However, unlike canonical genes, many transcripts from non-coding DNA have limited evidence of conservation or function. Here, to determine how much biological noise is expected from non-genic sequences, we quantify the regulatory activity of evolutionarily naive DNA using RNA-seq in yeast and computational predictions in humans. In yeast, more than 99% of naive DNA bases were transcribed. Unlike the evolved transcriptome, naive transcripts frequently overlapped with opposite sense transcripts, suggesting selection favored coherent gene structures in the yeast genome. In humans, regulation-associated chromatin activity is predicted to be common in naive dinucleotide-content-matched randomized DNA. Here, naive and evolved DNA have similar co-occurrence and cell-type specificity of chromatin marks, challenging these as indicators of selection. However, in both yeast and humans, extreme high activities were rare in naive DNA, suggesting they result from selection. Overall, basal regulatory activity seems to be the default, which selection can hone to evolve a function or, if detrimental, repress. Here, the authors ask how much regulatory activity DNA is expected to have in the absence of selection. In yeast and humans, they find that gene regulatory activity is common in evolutionarily naive DNA, suggesting that activity is not always indicative of function.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140043505","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}

引用次数: 0

Author Correction: Shifted PAMs generate DNA overhangs and enhance SpCas9 post-catalytic complex dissociation 作者更正：偏移的 PAM 产生 DNA 悬垂并增强 SpCas9 催化后复合物解离。

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-03-05 DOI: 10.1038/s41594-024-01247-0

Jinglong Wang, Julien Le Gall, Richard L. Frock, Terence R. Strick

引用次数: 0

Good reasons for structural biology 结构生物学的充分理由

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-03-01 DOI: 10.1038/s41594-024-01232-7

Patrick Cramer

引用次数: 0

Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition 与核糖体结合的 NR5A2 结构揭示了 DNA 小沟锚竞争的先驱因子机制

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-02-26 DOI: 10.1038/s41594-024-01239-0

Wataru Kobayashi, Anna H. Sappler, Daniel Bollschweiler, Maximilian Kümmecke, Jérôme Basquin, Eda Nur Arslantas, Siwat Ruangroengkulrith, Renate Hornberger, Karl Duderstadt, Kikuë Tachibana

{"title":"Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition","authors":"Wataru Kobayashi, Anna H. Sappler, Daniel Bollschweiler, Maximilian Kümmecke, Jérôme Basquin, Eda Nur Arslantas, Siwat Ruangroengkulrith, Renate Hornberger, Karl Duderstadt, Kikuë Tachibana","doi":"10.1038/s41594-024-01239-0","DOIUrl":"10.1038/s41594-024-01239-0","url":null,"abstract":"Gene expression during natural and induced reprogramming is controlled by pioneer transcription factors that initiate transcription from closed chromatin. Nr5a2 is a key pioneer factor that regulates zygotic genome activation in totipotent embryos, pluripotency in embryonic stem cells and metabolism in adult tissues, but the mechanism of its pioneer activity remains poorly understood. Here, we present a cryo-electron microscopy structure of human NR5A2 bound to a nucleosome. The structure shows that the conserved carboxy-terminal extension (CTE) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome and releases entry-exit site DNA. Mutational analysis showed that NR5A2 D159 of the CTE is dispensable for DNA binding but required for stable nucleosome association and persistent DNA ‘unwrapping’. These findings suggest that NR5A2 belongs to an emerging class of pioneer factors that can use DNA minor groove anchor competition to destabilize nucleosomes and facilitate gene expression during reprogramming. The authors determined a cryo-EM structure of the pioneer factor NR5A2 bound to a nucleosome. NR5A2 releases nucleosomal DNA from histones by DNA minor anchor groove competition, providing a mechanism for pioneer factor activity during reprogramming","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01239-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139967242","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}

引用次数: 0

The open gate of the AMPA receptor forms a Ca2+ binding site critical in regulating ion transport AMPA 受体的开放门形成一个 Ca2+ 结合位点，对调节离子转运至关重要

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-02-26 DOI: 10.1038/s41594-024-01228-3

Terunaga Nakagawa, Xin-tong Wang, Federico J. Miguez-Cabello, Derek Bowie

{"title":"The open gate of the AMPA receptor forms a Ca2+ binding site critical in regulating ion transport","authors":"Terunaga Nakagawa, Xin-tong Wang, Federico J. Miguez-Cabello, Derek Bowie","doi":"10.1038/s41594-024-01228-3","DOIUrl":"10.1038/s41594-024-01228-3","url":null,"abstract":"Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are cation-selective ion channels that mediate most fast excitatory neurotransmission in the brain. Although their gating mechanism has been studied extensively, understanding how cations traverse the pore has remained elusive. Here we investigated putative ion and water densities in the open pore of Ca2+-permeable AMPARs (rat GRIA2 flip-Q isoform) at 2.3–2.6 Å resolution. We show that the ion permeation pathway attains an extracellular Ca2+ binding site (site-G) when the channel gate moves into the open configuration. Site-G is highly selective for Ca2+ over Na+, favoring the movement of Ca2+ into the selectivity filter of the pore. Seizure-related N619K mutation, adjacent to site-G, promotes channel opening but attenuates Ca2+ binding and thus diminishes Ca2+ permeability. Our work identifies the importance of site-G, which coordinates with the Q/R site of the selectivity filter to ensure the preferential transport of Ca2+ through the channel pore. A calcium ion binding site, hidden in the highly conserved gate of the synaptic AMPA-type ionotropic glutamate receptor, reveals upon gating and controls ion transport across the membrane, providing new mechanistic insights on ion permeation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139967323","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}

引用次数: 0

The CNK–HYP scaffolding complex promotes RAF activation by enhancing KSR–MEK interaction CNK-HYP 支架复合物通过增强 KSR-MEK 相互作用促进 RAF 激活

IF 12.5 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-02-22 DOI: 10.1038/s41594-024-01233-6

Pierre Maisonneuve, Malha Sahmi, Fanny Bergeron-Labrecque, Xianjie Iris Ma, Juliette Queguiner, Geneviève Arseneault, Martin Lefrançois, Igor Kurinov, Rémi Fronzes, Frank Sicheri, Marc Therrien

{"title":"The CNK–HYP scaffolding complex promotes RAF activation by enhancing KSR–MEK interaction","authors":"Pierre Maisonneuve, Malha Sahmi, Fanny Bergeron-Labrecque, Xianjie Iris Ma, Juliette Queguiner, Geneviève Arseneault, Martin Lefrançois, Igor Kurinov, Rémi Fronzes, Frank Sicheri, Marc Therrien","doi":"10.1038/s41594-024-01233-6","DOIUrl":"10.1038/s41594-024-01233-6","url":null,"abstract":"The RAS–MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains only partially understood. There are three RAF isoforms in mammals (ARAF, BRAF and CRAF) and two related pseudokinases (KSR1 and KSR2). RAS-mediated activation of RAF depends on an allosteric mechanism driven by the dimerization of its kinase domain. Recent work on human RAFs showed that MEK binding to KSR1 promotes KSR1–BRAF heterodimerization, which leads to the phosphorylation of free MEK molecules by BRAF. Similar findings were made with the single Drosophila RAF homolog. Here we show that the fly scaffold proteins CNK and HYP stabilize the KSR–MEK interaction, which in turn enhances RAF–KSR heterodimerization and RAF activation. The cryogenic electron microscopy structure of the minimal KSR–MEK–CNK–HYP complex reveals a ring-like arrangement of the CNK–HYP complex allowing CNK to simultaneously engage KSR and MEK, thus stabilizing the binary interaction. Together, these results illuminate how CNK contributes to RAF activation by stimulating the allosteric function of KSR and highlight the diversity of mechanisms impacting RAF dimerization as well as the regulatory potential of the KSR–MEK interaction. Using biochemistry, cell biological, X-ray crystallography and cryo-EM methods, Maisonneuve et al. reveal how the scaffolding proteins CNK and HYP enhance the binding of KSR to MEK, which in turn allosterically controls RAF activation in Drosophila.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01233-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139917349","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}

引用次数: 0

Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis 人类鞘磷脂合成酶的低温电子显微镜结构及其对鞘磷脂合成的机理影响

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-02-22 DOI: 10.1038/s41594-024-01237-2

Kexin Hu, Qing Zhang, Yang Chen, Jintong Yang, Ying Xia, Bing Rao, Shaobai Li, Yafeng Shen, Mi Cao, Hongliang Lu, An Qin, Xian-Cheng Jiang, Deqiang Yao, Jie Zhao, Lu Zhou, Yu Cao

{"title":"Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis","authors":"Kexin Hu, Qing Zhang, Yang Chen, Jintong Yang, Ying Xia, Bing Rao, Shaobai Li, Yafeng Shen, Mi Cao, Hongliang Lu, An Qin, Xian-Cheng Jiang, Deqiang Yao, Jie Zhao, Lu Zhou, Yu Cao","doi":"10.1038/s41594-024-01237-2","DOIUrl":"10.1038/s41594-024-01237-2","url":null,"abstract":"Sphingomyelin (SM) has key roles in modulating mammalian membrane properties and serves as an important pool for bioactive molecules. SM biosynthesis is mediated by the sphingomyelin synthase (SMS) family, comprising SMS1, SMS2 and SMS-related (SMSr) members. Although SMS1 and SMS2 exhibit SMS activity, SMSr possesses ceramide phosphoethanolamine synthase activity. Here we determined the cryo-electron microscopic structures of human SMSr in complexes with ceramide, diacylglycerol/phosphoethanolamine and ceramide/phosphoethanolamine (CPE). The structures revealed a hexameric arrangement with a reaction chamber located between the transmembrane helices. Within this structure, a catalytic pentad E–H/D–H–D was identified, situated at the interface between the lipophilic and hydrophilic segments of the reaction chamber. Additionally, the study unveiled the two-step synthesis process catalyzed by SMSr, involving PE–PLC (phosphatidylethanolamine–phospholipase C) hydrolysis and the subsequent transfer of the phosphoethanolamine moiety to ceramide. This research provides insights into the catalytic mechanism of SMSr and expands our understanding of sphingolipid metabolism. Researchers unveiled the structural details of sphingomyelin synthase (SMSr), shedding light on its role in sphingolipid biosynthesis. SMSr transfers the phosphoethanolamine from PE to ceramide, adding complexity to the field of lipid homeostasis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139917214","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}

引用次数: 0

Deadenylation kinetics of mixed poly(A) tails at single-nucleotide resolution 单核苷酸分辨率下混合聚（A）尾的去烯化动力学

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-02-19 DOI: 10.1038/s41594-023-01187-1

Young-suk Lee, Yevgen Levdansky, Yoonseok Jung, V. Narry Kim, Eugene Valkov

{"title":"Deadenylation kinetics of mixed poly(A) tails at single-nucleotide resolution","authors":"Young-suk Lee, Yevgen Levdansky, Yoonseok Jung, V. Narry Kim, Eugene Valkov","doi":"10.1038/s41594-023-01187-1","DOIUrl":"10.1038/s41594-023-01187-1","url":null,"abstract":"Shortening of messenger RNA poly(A) tails, or deadenylation, is a rate-limiting step in mRNA decay and is highly regulated during gene expression. The incorporation of non-adenosines in poly(A) tails, or ‘mixed tailing’, has been observed in vertebrates and viruses. Here, to quantitate the effect of mixed tails, we mathematically modeled deadenylation reactions at single-nucleotide resolution using an in vitro deadenylation system reconstituted with the complete human CCR4–NOT complex. Applying this model, we assessed the disrupting impact of single guanosine, uridine or cytosine to be equivalent to approximately 6, 8 or 11 adenosines, respectively. CCR4–NOT stalls at the 0, −1 and −2 positions relative to the non-adenosine residue. CAF1 and CCR4 enzyme subunits commonly prefer adenosine but exhibit distinct sequence selectivities and stalling positions. Our study provides an analytical framework to monitor deadenylation and reveals the molecular basis of tail sequence-dependent regulation of mRNA stability. Here, using mathematical modeling and an in vitro deadenylation system, the authors quantitatively demonstrate the effect of non-adenosines in the poly(A) tail and exemplify how tail sequence regulates mRNA stability.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-023-01187-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139901755","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}

引用次数: 0

Ubiquitin in autophagy and non-protein ubiquitination 自噬和非蛋白质泛素化中的泛素

IF 16.8 1区生物学

Nature Structural & Molecular Biology Pub Date : 2024-02-16 DOI: 10.1038/s41594-024-01217-6

Noboru Mizushima

引用次数: 0