Nature structural & molecular biology最新文献

Uncovering protein glycosylation dynamics and heterogeneity using deep quantitative glycoprofiling (DQGlyco)

Nature structural & molecular biology Pub Date : 2025-02-10 DOI: 10.1038/s41594-025-01485-w

Clément M. Potel, Mira Lea Burtscher, Martin Garrido-Rodriguez, Amber Brauer-Nikonow, Isabelle Becher, Cecile Le Sueur, Athanasios Typas, Michael Zimmermann, Mikhail M. Savitski

{"title":"Uncovering protein glycosylation dynamics and heterogeneity using deep quantitative glycoprofiling (DQGlyco)","authors":"Clément M. Potel, Mira Lea Burtscher, Martin Garrido-Rodriguez, Amber Brauer-Nikonow, Isabelle Becher, Cecile Le Sueur, Athanasios Typas, Michael Zimmermann, Mikhail M. Savitski","doi":"10.1038/s41594-025-01485-w","DOIUrl":"https://doi.org/10.1038/s41594-025-01485-w","url":null,"abstract":"Protein glycosylation regulates essential cellular processes such as signaling, adhesion and cell–cell interactions; however, dysregulated glycosylation is associated with diseases such as cancer. Here we introduce deep quantitative glycoprofiling (DQGlyco), a robust method that integrates high-throughput sample preparation, highly sensitive detection and precise multiplexed quantification to investigate protein glycosylation dynamics at an unprecedented depth. Using DQGlyco, we profiled the mouse brain glycoproteome, identifying 177,198 unique N-glycopeptides—25 times more than previous studies. We quantified glycopeptide changes in human cells treated with a fucosylation inhibitor and characterized surface-exposed glycoforms. Furthermore, we analyzed tissue-specific glycosylation patterns in mice and demonstrated that a defined gut microbiota substantially remodels the mouse brain glycoproteome, shedding light on the link between the gut microbiome and brain protein functions. Additionally, we developed a novel strategy to evaluate glycoform solubility, offering new insights into their biophysical properties. Overall, the in-depth profiling offered by DQGlyco uncovered extensive complexity in glycosylation regulation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375427","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}

引用次数: 0

Initiation of ERAD by the bifunctional complex of Mnl1/Htm1 mannosidase and protein disulfide isomerase

Nature structural & molecular biology Pub Date : 2025-02-10 DOI: 10.1038/s41594-025-01491-y

Dan Zhao, Xudong Wu, Tom A. Rapoport

引用次数: 0

Multiple allosteric mechanisms suppress PRC2 activity at active genes

Nature structural & molecular biology Pub Date : 2025-02-06 DOI: 10.1038/s41594-025-01487-8

Evan J. Worden

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Structural basis of circularly permuted group II intron self-splicing

Nature structural & molecular biology Pub Date : 2025-01-31 DOI: 10.1038/s41594-025-01484-x

Liu Wang, Jiahao Xie, Chong Zhang, Jian Zou, Zirui Huang, Sitong Shang, Xingyu Chen, Yang Yang, Jianquan Liu, Haohao Dong, Dingming Huang, Zhaoming Su

{"title":"Structural basis of circularly permuted group II intron self-splicing","authors":"Liu Wang, Jiahao Xie, Chong Zhang, Jian Zou, Zirui Huang, Sitong Shang, Xingyu Chen, Yang Yang, Jianquan Liu, Haohao Dong, Dingming Huang, Zhaoming Su","doi":"10.1038/s41594-025-01484-x","DOIUrl":"https://doi.org/10.1038/s41594-025-01484-x","url":null,"abstract":"Circularly permuted group II introns (CP introns) consist of rearranged structural domains separated by two tethered exons, generating branched introns and circular exons via back-splicing. Structural and mechanistic understanding of circular RNA (circRNA) generation by CP introns remains elusive. We resolve cryo-electron microscopy structures of a natural CP intron in different states during back-splicing at a resolution of 2.5–2.9 Å. Domain 6 (D6) undergoes a conformational change of 65° after branching, to facilitate 3′-exon recognition and circularization. Previously unseen tertiary interactions compact the catalytic triad and D6 for splicing without protein, whereas a metal ion, M35, is observed to stabilize the 5′-exon during splicing. While these unique features were not observed in canonical group II introns and spliceosomes, they are common in CP introns, as demonstrated by the cryo-EM structure of another CP intron discovered by comparative genomics analysis. Our results elucidate the mechanism of CP intron back-splicing dynamics, with potential applications in circRNA research and therapeutics.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071970","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}

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A network of interacting ciliary tip proteins with opposing activities imparts slow and processive microtubule growth

Nature structural & molecular biology Pub Date : 2025-01-24 DOI: 10.1038/s41594-025-01483-y

Harriet A. J. Saunders, Cyntha M. van den Berg, Robin A. Hoogebeen, Donna Schweizer, Kelly E. Stecker, Ronald Roepman, Stuart C. Howes, Anna Akhmanova

{"title":"A network of interacting ciliary tip proteins with opposing activities imparts slow and processive microtubule growth","authors":"Harriet A. J. Saunders, Cyntha M. van den Berg, Robin A. Hoogebeen, Donna Schweizer, Kelly E. Stecker, Ronald Roepman, Stuart C. Howes, Anna Akhmanova","doi":"10.1038/s41594-025-01483-y","DOIUrl":"https://doi.org/10.1038/s41594-025-01483-y","url":null,"abstract":"Cilia are motile or sensory organelles present on many eukaryotic cells. Their formation and function rely on axonemal microtubules, which exhibit very slow dynamics, but the underlying mechanisms are largely unexplored. Here we reconstituted in vitro the individual and collective activities of the ciliary tip module proteins CEP104, CSPP1, TOGARAM1, ARMC9 and CCDC66, which interact with each other and with microtubules and, when mutated in humans, cause ciliopathies such as Joubert syndrome. We show that CEP104, a protein with a tubulin-binding TOG domain, and its luminal partner CSPP1 inhibit microtubule growth and shortening. Another TOG-domain protein, TOGARAM1, overcomes growth inhibition imposed by CEP104 and CSPP1. CCDC66 and ARMC9 do not affect microtubule dynamics but act as scaffolds for their partners. Cryo-electron tomography demonstrated that, together, ciliary tip module members form plus-end-specific cork-like structures that reduce protofilament flaring. The combined effect of these proteins is very slow processive microtubule elongation, which recapitulates axonemal dynamics in cells.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027263","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}

引用次数: 0

Cryo-EM structure of the NDH–PSI–LHCI supercomplex from Spinacia oleracea

Nature structural & molecular biology Pub Date : 2025-01-24 DOI: 10.1038/s41594-024-01478-1

Bianca Introini, Alexander Hahn, Werner Kühlbrandt

引用次数: 0

Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring 补体C3的低温电镜分析显示巨球蛋白环有一个可逆的大开口

Nature structural & molecular biology Pub Date : 2025-01-23 DOI: 10.1038/s41594-024-01467-4

Trine Amalie Fogh Gadeberg, Martin Høgholm Jørgensen, Heidi Gytz Olesen, Josefine Lorentzen, Seandean Lykke Harwood, Ana Viana Almeida, Marlene Uglebjerg Fruergaard, Rasmus Kjeldsen Jensen, Philipp Kanis, Henrik Pedersen, Emil Tranchant, Steen Vang Petersen, Ida Buch Thøgersen, Birthe Brandt Kragelund, Joseph Anthony Lyons, Jan Johannes Enghild, Gregers Rom Andersen

{"title":"Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring","authors":"Trine Amalie Fogh Gadeberg, Martin Høgholm Jørgensen, Heidi Gytz Olesen, Josefine Lorentzen, Seandean Lykke Harwood, Ana Viana Almeida, Marlene Uglebjerg Fruergaard, Rasmus Kjeldsen Jensen, Philipp Kanis, Henrik Pedersen, Emil Tranchant, Steen Vang Petersen, Ida Buch Thøgersen, Birthe Brandt Kragelund, Joseph Anthony Lyons, Jan Johannes Enghild, Gregers Rom Andersen","doi":"10.1038/s41594-024-01467-4","DOIUrl":"https://doi.org/10.1038/s41594-024-01467-4","url":null,"abstract":"The C3 protein is the central molecule within the complement system and undergoes proteolytic activation to C3b in the presence of pathogens. Pattern-independent activation of C3 also occurs via hydrolysis, resulting in C3(H2O), but the structural details of C3 hydrolysis remain elusive. Here we show that the conformation of the C3(H2O) analog, C3MA, is indistinguishable from C3b. In contrast, the reaction intermediate C3* adopts a conformation dramatically different from both C3 and C3MA. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG ring through which the anaphylatoxin (ANA) domain translocates through a transient opening. C3MA formation is inhibited by an MG3-specific nanobody and prevented by linking the ANA domain to the C3 β-chain. Our study reveals an unexpected dynamic behavior of C3 and forms the basis for elucidation of the in vivo contribution of C3 hydrolysis and for controlling complement upon intravascular hemolysis and surface-contact-induced activation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020651","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}

引用次数: 0

ELL3 regulates spindle assembly to prevent maternally inherited aneuploidy and infertility ELL3调节纺锤体组装以防止母体遗传的非整倍体和不孕症

Nature structural & molecular biology Pub Date : 2025-01-22 DOI: 10.1038/s41594-024-01475-4

Bernhard Magerl, Tommaso Cavazza

引用次数: 0

The conformational landscape of human transthyretin revealed by cryo-EM 低温电镜显示的人甲状腺素的构象景观

Nature structural & molecular biology Pub Date : 2025-01-22 DOI: 10.1038/s41594-024-01472-7

Benjamin Basanta, Karina Nugroho, Nicholas L. Yan, Gabriel M. Kline, Evan T. Powers, Felix J. Tsai, Mengyu Wu, Althea Hansel-Harris, Jason S. Chen, Stefano Forli, Jeffrey W. Kelly, Gabriel C. Lander

引用次数: 0

Temporal and regional X-linked gene reactivation in the mouse germline reveals site-specific retention of epigenetic silencing 小鼠种系中时间和区域x连锁基因的再激活揭示了表观遗传沉默的位点特异性保留

Nature structural & molecular biology Pub Date : 2025-01-21 DOI: 10.1038/s41594-024-01469-2

Clara Roidor, Laurène Syx, Emmanuelle Beyne, Peggy Raynaud, Dina Zielinski, Aurélie Teissandier, Caroline Lee, Marius Walter, Nicolas Servant, Karim Chebli, Deborah Bourc’his, M. Azim Surani, Maud Borensztein

{"title":"Temporal and regional X-linked gene reactivation in the mouse germline reveals site-specific retention of epigenetic silencing","authors":"Clara Roidor, Laurène Syx, Emmanuelle Beyne, Peggy Raynaud, Dina Zielinski, Aurélie Teissandier, Caroline Lee, Marius Walter, Nicolas Servant, Karim Chebli, Deborah Bourc’his, M. Azim Surani, Maud Borensztein","doi":"10.1038/s41594-024-01469-2","DOIUrl":"https://doi.org/10.1038/s41594-024-01469-2","url":null,"abstract":"Random X-chromosome inactivation is a hallmark of female mammalian somatic cells. This epigenetic mechanism, mediated by the long noncoding RNA Xist, occurs in the early embryo and is stably maintained throughout life, although inactivation is lost during primordial germ cell (PGC) development. Using a combination of single-cell allele-specific RNA sequencing and low-input chromatin profiling on developing mouse PGCs, we provide a detailed map of X-linked gene reactivation. Despite the absence of Xist expression, PGCs still harbor a fully silent X chromosome at embryonic day 9.5 (E9.5). Subsequently, X-linked genes undergo gradual and distinct regional reactivation. At E12.5, a substantial part of the inactive X chromosome resists reactivation, retaining an epigenetic memory of its silencing. Our findings define the orchestration of reactivation of the inactive X chromosome, a key event in female PGC reprogramming with direct implications for reproduction.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990653","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}

引用次数: 0