Si Hoon Park, Juhyun Han, Byung-Cheon Jeong, Ju Han Song, Se Hwan Jang, Hyeongseop Jeong, Bong Heon Kim, Young-Gyu Ko, Zee-Yong Park, Kyung Eun Lee, Jaekyung Hyun, Hyun Kyu Song
{"title":"Publisher Correction: Structure and activation of the RING E3 ubiquitin ligase TRIM72 on the membrane.","authors":"Si Hoon Park, Juhyun Han, Byung-Cheon Jeong, Ju Han Song, Se Hwan Jang, Hyeongseop Jeong, Bong Heon Kim, Young-Gyu Ko, Zee-Yong Park, Kyung Eun Lee, Jaekyung Hyun, Hyun Kyu Song","doi":"10.1038/s41594-024-01429-w","DOIUrl":"https://doi.org/10.1038/s41594-024-01429-w","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522481","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}
Li Li, Mariia Yu Rybak, Jinzhong Lin, Matthieu G Gagnon
{"title":"The ribosome termination complex remodels release factor RF3 and ejects GDP.","authors":"Li Li, Mariia Yu Rybak, Jinzhong Lin, Matthieu G Gagnon","doi":"10.1038/s41594-024-01360-0","DOIUrl":"10.1038/s41594-024-01360-0","url":null,"abstract":"<p><p>Translation termination involves release factors RF1, RF2 and the GTPase RF3 that recycles RF1 and RF2 from the ribosome. RF3 dissociates from the ribosome in the GDP-bound form and must then exchange GDP for GTP. The 70S ribosome termination complex (70S-TC) accelerates GDP exchange in RF3, suggesting that the 70S-TC can function as the guanine nucleotide exchange factor for RF3. Here, we use cryogenic-electron microscopy to elucidate the mechanism of GDP dissociation from RF3 catalyzed by the Escherichia coli 70S-TC. The non-rotated ribosome bound to RF1 remodels RF3 and induces a peptide flip in the phosphate-binding loop, efficiently ejecting GDP. Binding of GTP allows RF3 to dock at the GTPase center, promoting the dissociation of RF1 from the ribosome. The structures recapitulate the functional cycle of RF3 on the ribosome and uncover the mechanism by which the 70S-TC allosterically dismantles the phosphate-binding groove in RF3, a previously overlooked function of the ribosome.</p>","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727534","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}
{"title":"Structural basis of NEAT1 lncRNA maturation and menRNA instability.","authors":"Ilias Skeparnias, Jinwei Zhang","doi":"10.1038/s41594-024-01361-z","DOIUrl":"https://doi.org/10.1038/s41594-024-01361-z","url":null,"abstract":"<p><p>NEAT1 long noncoding RNA orchestrates paraspeckle assembly and impacts tumorigenesis, fertility and immunity. Its maturation requires RNase P cleavage yielding an unstable transfer RNA-like multiple endocrine neoplasia-β tRNA-like transcript (menRNA) due to CCACCA addition. Here we report the crystal structure of human menRNA, which partially mimics tRNAs to drive RNase P and ELAC2 processing. Biophysical analyses uncover an RNA-centric, riboswitch-like mechanism whereby the nascent CCA reshapes the RNA folding landscape and propels a spontaneous conformational isomerization that directs repeat CCA addition, marking the menRNA and defective tRNAs for degradation.</p>","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723984","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}
D. Snead, M. Matyszewski, Andrea M. Dickey, Yu Lin, A. Leschziner, Samara L. Reck-Peterson
{"title":"Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules","authors":"D. Snead, M. Matyszewski, Andrea M. Dickey, Yu Lin, A. Leschziner, Samara L. Reck-Peterson","doi":"10.1101/2022.01.21.477284","DOIUrl":"https://doi.org/10.1101/2022.01.21.477284","url":null,"abstract":"Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson’s Disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-electron microscopy structure of the catalytic half of LRRK2, containing its kinase, which is in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2, but is not linked to PD. LRRK1’s structure is similar to LRRK2, but LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2’s GTPase domain that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2’s kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2022-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41446644","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}
K. Tsai, Vanja Stojković, D. J. Lee, Iris D. Young, Teresa Szal, N. Vázquez-Laslop, A. Mankin, James S. Fraser, D. Fujimori
{"title":"Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics","authors":"K. Tsai, Vanja Stojković, D. J. Lee, Iris D. Young, Teresa Szal, N. Vázquez-Laslop, A. Mankin, James S. Fraser, D. Fujimori","doi":"10.1101/2021.08.10.455846","DOIUrl":"https://doi.org/10.1101/2021.08.10.455846","url":null,"abstract":"The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. In this study, we determined that the second-generation oxazolidinone radezolid also induces stalling with alanine at the penultimate position. However, the molecular basis for context-specificity of these inhibitors has not been elucidated. In this study, we determined high-resolution cryo-EM structures of both linezolid and radezolid-stalled ribosome complexes. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling by forcing the antibiotic to adopt a conformation that narrows the hydrophobic alanine pocket. Together, the structural and biochemical findings presented in this work provide molecular understanding of context-specific inhibition of translation by clinically important oxazolidinone antibiotics.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2021-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"62332424","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}
{"title":"Higher-order phosphatase–substrate contacts terminate the integrated stress response","authors":"Yahui Yan, H. Harding, D. Ron","doi":"10.1101/2021.06.18.449003","DOIUrl":"https://doi.org/10.1101/2021.06.18.449003","url":null,"abstract":"Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c–PPP1R15A–G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR. Structures of the dephosphorylation complex for phosphorylated eIF2α reveal how contacts with the regulatory PPP1R15A subunit mediate substrate selectivity, providing a paradigm for dephosphorylation reactions by diverse combinatorially assembled holophosphatases.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2021-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49110087","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}
{"title":"Structural basis of nucleosome transcription mediated by Chd1 and FACT","authors":"L. Farnung, M. Ochmann, M. Engeholm, P. Cramer","doi":"10.1101/2020.11.30.403857","DOIUrl":"https://doi.org/10.1101/2020.11.30.403857","url":null,"abstract":"Efficient transcription of RNA polymerase II (Pol II) through nucleosomes requires the help of various factors. Here we show biochemically that Pol II transcription through a nucleosome is facilitated by the chromatin remodeler Chd1 and the histone chaperone FACT when the elongation factors Spt4/5 and TFIIS are present. We report cryo-EM structures of transcribing Saccharomyces cerevisiae Pol II−Spt4/5−nucleosome complexes with bound Chd1 or FACT. In the first structure, Pol II transcription exposes the proximal histone H2A−H2B dimer that is bound by Spt5. Pol II has also released the inhibitory DNA-binding region of Chd1 that is poised to pump DNA toward Pol II. In the second structure, Pol II has generated a partially unraveled nucleosome that binds FACT, which excludes Chd1 and Spt5. These results suggest that Pol II progression through a nucleosome activates Chd1, enables FACT binding and eventually triggers transfer of FACT together with histones to upstream DNA. Structural and functional analyses of RNA polymerase II−nucleosome complexes reveal how the chromatin remodeler Chd1 and the histone chaperone FACT mediate Pol II transcription through a nucleosome.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2020-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42190486","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}
M. Girbig, A. Misiaszek, Matthias K. Vorländer, Aleix Lafita, H. Grötsch, F. Baudin, A. Bateman, C. Müller
{"title":"Cryo-EM structures of human RNA polymerase III in its unbound and transcribing states","authors":"M. Girbig, A. Misiaszek, Matthias K. Vorländer, Aleix Lafita, H. Grötsch, F. Baudin, A. Bateman, C. Müller","doi":"10.1101/2020.06.29.177642","DOIUrl":"https://doi.org/10.1101/2020.06.29.177642","url":null,"abstract":"RNA polymerase III (Pol III) synthesizes transfer RNAs and other short, essential RNAs. Human Pol III misregulation is linked to tumor transformation, neurodegenerative and developmental disorders, and increased sensitivity to viral infections. Here, we present cryo-electron microscopy structures at 2.8 to 3.3 Å resolution of transcribing and unbound human Pol III. We observe insertion of the TFIIS-like subunit RPC10 into the polymerase funnel, providing insights into how RPC10 triggers transcription termination. Our structures resolve elements absent from Saccharomyces cerevisiae Pol III such as the winged-helix domains of RPC5 and an iron–sulfur cluster, which tethers the heterotrimer subcomplex to the core. The cancer-associated RPC7α isoform binds the polymerase clamp, potentially interfering with Pol III inhibition by tumor suppressor MAF1, which may explain why overexpressed RPC7α enhances tumor transformation. Finally, the human Pol III structure allows mapping of disease-related mutations and may contribute to the development of inhibitors that selectively target Pol III for therapeutic interventions. Cryo-EM structures of human Pol III in both apo- and elongating states reveal metazoan-specific differences in the regulation of transcription termination and identify mutations relevant to human disease.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":null,"pages":null},"PeriodicalIF":16.8,"publicationDate":"2020-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42310095","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}