Lührmann, Reinhard

[["dc.bibliographiccitation.firstpage","2416"],["dc.bibliographiccitation.issue","23-24"],["dc.bibliographiccitation.journal","Genes & Development"],["dc.bibliographiccitation.lastpage","2429"],["dc.bibliographiccitation.volume","31"],["dc.contributor.author","Bao, Penghui"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Boon, Kum-Loong"],["dc.contributor.author","Lührmann, Reinhard"],["dc.date.accessioned","2020-12-10T18:20:20Z"],["dc.date.available","2020-12-10T18:20:20Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1101/gad.308163.117"],["dc.identifier.eissn","1549-5477"],["dc.identifier.issn","0890-9369"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/75524"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","The RES complex is required for efficient transformation of the precatalytic B spliceosome into an activated B act complex"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","5528"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","Molecular and Cellular Biology"],["dc.bibliographiccitation.lastpage","5543"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Deckert, Jochen"],["dc.contributor.author","Hartmuth, Klaus"],["dc.contributor.author","Boehringer, Daniel"],["dc.contributor.author","Behzadnia, Nastaran"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Kastner, Berthold"],["dc.contributor.author","Stark, Holger"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Lührmann, Reinhard"],["dc.date.accessioned","2021-03-05T08:59:02Z"],["dc.date.available","2021-03-05T08:59:02Z"],["dc.date.issued","2006"],["dc.identifier.doi","10.1128/MCB.00582-06"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/80332"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.eissn","1098-5549"],["dc.relation.issn","0270-7306"],["dc.title","Protein Composition and Electron Microscopy Structure of Affinity-Purified Human Spliceosomal B Complexes Isolated under Physiological Conditions"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","296"],["dc.bibliographiccitation.issue","7871"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","300"],["dc.bibliographiccitation.volume","596"],["dc.contributor.author","Zhang, Zhenwei"],["dc.contributor.author","Rigo, Norbert"],["dc.contributor.author","Dybkov, Olexandr"],["dc.contributor.author","Fourmann, Jean-Baptiste"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Kumar, Vinay"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Stark, Holger"],["dc.contributor.author","Lührmann, Reinhard"],["dc.date.accessioned","2021-09-01T06:42:22Z"],["dc.date.available","2021-09-01T06:42:22Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract During the splicing of introns from precursor messenger RNAs (pre-mRNAs), the U2 small nuclear ribonucleoprotein (snRNP) must undergo stable integration into the spliceosomal A complex—a poorly understood, multistep process that is facilitated by the DEAD-box helicase Prp5 (refs. 1–4 ). During this process, the U2 small nuclear RNA (snRNA) forms an RNA duplex with the pre-mRNA branch site (the U2–BS helix), which is proofread by Prp5 at this stage through an unclear mechanism 5 . Here, by deleting the branch-site adenosine (BS-A) or mutating the branch-site sequence of an actin pre-mRNA, we stall the assembly of spliceosomes in extracts from the yeast Saccharomyces cerevisiae directly before the A complex is formed. We then determine the three-dimensional structure of this newly identified assembly intermediate by cryo-electron microscopy. Our structure indicates that the U2–BS helix has formed in this pre-A complex, but is not yet clamped by the HEAT domain of the Hsh155 protein (Hsh155 HEAT ), which exhibits an open conformation. The structure further reveals a large-scale remodelling/repositioning of the U1 and U2 snRNPs during the formation of the A complex that is required to allow subsequent binding of the U4/U6.U5 tri-snRNP, but that this repositioning is blocked in the pre-A complex by the presence of Prp5. Our data suggest that binding of Hsh155 HEAT to the bulged BS-A of the U2–BS helix triggers closure of Hsh155 HEAT , which in turn destabilizes Prp5 binding. Thus, Prp5 proofreads the branch site indirectly, hindering spliceosome assembly if branch-site mutations prevent the remodelling of Hsh155 HEAT . Our data provide structural insights into how a spliceosomal helicase enhances the fidelity of pre-mRNA splicing."],["dc.description.abstract","Abstract During the splicing of introns from precursor messenger RNAs (pre-mRNAs), the U2 small nuclear ribonucleoprotein (snRNP) must undergo stable integration into the spliceosomal A complex—a poorly understood, multistep process that is facilitated by the DEAD-box helicase Prp5 (refs. 1–4 ). During this process, the U2 small nuclear RNA (snRNA) forms an RNA duplex with the pre-mRNA branch site (the U2–BS helix), which is proofread by Prp5 at this stage through an unclear mechanism 5 . Here, by deleting the branch-site adenosine (BS-A) or mutating the branch-site sequence of an actin pre-mRNA, we stall the assembly of spliceosomes in extracts from the yeast Saccharomyces cerevisiae directly before the A complex is formed. We then determine the three-dimensional structure of this newly identified assembly intermediate by cryo-electron microscopy. Our structure indicates that the U2–BS helix has formed in this pre-A complex, but is not yet clamped by the HEAT domain of the Hsh155 protein (Hsh155 HEAT ), which exhibits an open conformation. The structure further reveals a large-scale remodelling/repositioning of the U1 and U2 snRNPs during the formation of the A complex that is required to allow subsequent binding of the U4/U6.U5 tri-snRNP, but that this repositioning is blocked in the pre-A complex by the presence of Prp5. Our data suggest that binding of Hsh155 HEAT to the bulged BS-A of the U2–BS helix triggers closure of Hsh155 HEAT , which in turn destabilizes Prp5 binding. Thus, Prp5 proofreads the branch site indirectly, hindering spliceosome assembly if branch-site mutations prevent the remodelling of Hsh155 HEAT . Our data provide structural insights into how a spliceosomal helicase enhances the fidelity of pre-mRNA splicing."],["dc.identifier.doi","10.1038/s41586-021-03789-5"],["dc.identifier.pii","3789"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89039"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-455"],["dc.relation.eissn","1476-4687"],["dc.relation.issn","0028-0836"],["dc.title","Structural insights into how Prp5 proofreads the pre-mRNA branch site"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","318"],["dc.bibliographiccitation.issue","7641"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.volume","542"],["dc.contributor.author","Bertram, Karl"],["dc.contributor.author","Agafonov, Dmitry E."],["dc.contributor.author","Liu, Wen-Ti"],["dc.contributor.author","Dybkov, Olexandr"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Hartmuth, Klaus"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Kastner, Berthold"],["dc.contributor.author","Stark, Holger"],["dc.contributor.author","Lührmann, Reinhard"],["dc.date.accessioned","2018-11-07T10:27:23Z"],["dc.date.available","2018-11-07T10:27:23Z"],["dc.date.issued","2017"],["dc.description.abstract","Spliceosome rearrangements facilitated by RNA helicase PRP16 before catalytic step two of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after PRP16 action (C ). The architecture of the catalytic U2-U6 ribonucleoprotein (RNP) core of the human C spliceosome is very similar to that of the yeast pre-Prp16 C complex. However, in C the branched intron region is separated from the catalytic centre by approximately 20 angstrom, and its position close to the U6 small nuclear RNA ACAGA box is stabilized by interactions with the PRP8 RNase H-like and PRP17 WD40 domains. RNA helicase PRP22 is located about 100 angstrom from the catalytic centre, suggesting that it destabilizes the spliced mRNA after step two from a distance. Comparison of the structure of the yeast C and human C complexes reveals numerous RNP rearrangements that are likely to be facilitated by PRP16, including a large-scale movement of the U2 small nuclear RNP."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [SFB 860]"],["dc.identifier.doi","10.1038/nature21079"],["dc.identifier.isi","000394451600030"],["dc.identifier.pmid","28076346"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43225"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1476-4687"],["dc.relation.issn","0028-0836"],["dc.title","Cryo-EM structure of a human spliceosome activated for step 2 of splicing"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","869"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Molecular Cell"],["dc.bibliographiccitation.lastpage","883"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Golas, Monika M."],["dc.contributor.author","Sander, Bjoern"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Lührmann, Reinhard"],["dc.contributor.author","Stark, Holger"],["dc.date.accessioned","2021-03-05T08:58:09Z"],["dc.date.available","2021-03-05T08:58:09Z"],["dc.date.issued","2005"],["dc.identifier.doi","10.1016/j.molcel.2005.02.016"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/80024"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.issn","1097-2765"],["dc.title","Major Conformational Change in the Complex SF3b upon Integration into the Spliceosomal U11/U12 di-snRNP as Revealed by Electron Cryomicroscopy"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1329"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","RNA"],["dc.bibliographiccitation.lastpage","1337"],["dc.bibliographiccitation.volume","22"],["dc.contributor.author","Agafonov, Dmitry E."],["dc.contributor.author","van Santen, Marieke"],["dc.contributor.author","Kastner, Berthold"],["dc.contributor.author","Dube, Prakash"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Luehrmann, Reinhard"],["dc.date.accessioned","2018-11-07T10:09:55Z"],["dc.date.available","2018-11-07T10:09:55Z"],["dc.date.issued","2016"],["dc.description.abstract","The ATP analog ATP gamma S inhibits pre-mRNA splicing in vitro, but there have been conflicting reports as to which step of splicing is inhibited by this small molecule and its inhibitory mechanism remains unclear. Here we have dissected the effect of ATP gamma S on pre-mRNA splicing in vitro. Addition of ATP gamma S to splicing extracts depleted of ATP inhibited both catalytic steps of splicing. At ATP gamma S concentrations >= 0.5 mM, precatalytic B complexes accumulate, demonstrating a block prior to or during the spliceosome activation stage. Affinity purification of the ATP gamma S-stalled B complexes (B-ATP gamma S) and subsequent characterization of their abundant protein components by 2D gel electrophoresis revealed that B-ATP gamma S complexes are compositionally more homogeneous than B complexes previously isolated in the presence of ATP. In particular, they contain little or no Prp19/CDC5L complex proteins, indicating that these proteins are recruited after assembly of the precatalytic spliceosome. Under the electron microscope, B-ATP gamma S complexes exhibit a morphology highly similar to B complexes, indicating that the ATP gamma S-induced block in the transformation of the B to B-act complex is not due to a major structural defect. Likely mechanisms whereby ATP gamma S blocks spliceosome assembly at the activation stage, including inhibition of the RNA helicase Brr2, are discussed. Given their more homogeneous composition, B complexes stalled by ATP gamma S may prove highly useful for both functional and structural analyses of the precatalytic spliceosome and its conversion into an activated B-act spliceosomal complex."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG) [LU294/15-1]"],["dc.identifier.doi","10.1261/rna.057810.116"],["dc.identifier.isi","000381957100005"],["dc.identifier.pmid","27411562"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39746"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cold Spring Harbor Lab Press, Publications Dept"],["dc.relation.issn","1469-9001"],["dc.relation.issn","1355-8382"],["dc.title","ATP gamma S stalls splicing after B complex formation but prior to spliceosome activation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","310"],["dc.bibliographiccitation.issue","7815"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","313"],["dc.bibliographiccitation.volume","583"],["dc.contributor.author","Zhang, Zhenwei"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Bertram, Karl"],["dc.contributor.author","Dybkov, Olexandr"],["dc.contributor.author","Hartmuth, Klaus"],["dc.contributor.author","Agafonov, Dmitry E."],["dc.contributor.author","Hofele, Romina"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Kastner, Berthold"],["dc.contributor.author","Lührmann, Reinhard"],["dc.contributor.author","Stark, Holger"],["dc.date.accessioned","2021-04-14T08:25:47Z"],["dc.date.available","2021-04-14T08:25:47Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1038/s41586-020-2344-3"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81730"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.eissn","1476-4687"],["dc.relation.issn","0028-0836"],["dc.title","Molecular architecture of the human 17S U2 snRNP"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","307"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Molecular Cell"],["dc.bibliographiccitation.lastpage","319"],["dc.bibliographiccitation.volume","64"],["dc.contributor.author","Cretu, Constantin"],["dc.contributor.author","Schmitzova, Jana"],["dc.contributor.author","Ponce-Salvatierra, Almudena"],["dc.contributor.author","Dybkov, Olexandr"],["dc.contributor.author","De laurentiis, Evelina I."],["dc.contributor.author","Sharma, Kundan"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Lührmann, Reinhard"],["dc.contributor.author","Pena, Vladimir"],["dc.date.accessioned","2018-11-07T10:06:55Z"],["dc.date.available","2018-11-07T10:06:55Z"],["dc.date.issued","2016"],["dc.description.abstract","SF3b is a heptameric protein complex of the U2 small nuclear ribonucleoprotein (snRNP) that is essential for pre-mRNA splicing. Mutations in the largest SF3b subunit, SF3B1/SF3b155, are linked to cancer and lead to alternative branch site (BS) selection. Here we report the crystal structure of a human SF3b core complex, revealing how the distinctive conformation of SF3b155's HEAT domain is maintained by multiple contacts with SF3b130, SF3b10, and SF3b14b. Protein-protein crosslinking enabled the localization of the BS-binding proteins p14 and U2AF65 within SF3b155's HEAT-repeat superhelix, which together with SF3b14b forms a composite RNA-binding platform. SF3b155 residues, the mutation of which leads to cancer, contribute to the tertiary structure of the HEAT superhelix and its surface properties in the proximity of p14 and U2AF65. The molecular architecture of SF3b reveals the spatial organization of cancer-related SF3b155 mutations and advances our understanding of their effects on SF3b structure and function."],["dc.identifier.doi","10.1016/j.molcel.2016.08.036"],["dc.identifier.isi","000389515000011"],["dc.identifier.pmid","27720643"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39188"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","1097-4164"],["dc.relation.issn","1097-2765"],["dc.title","Molecular Architecture of SF3b and Structural Consequences of Its Cancer-Related Mutations"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1737"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.lastpage","1748"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Behzadnia, Nastaran"],["dc.contributor.author","Golas, Monika M."],["dc.contributor.author","Hartmuth, Klaus"],["dc.contributor.author","Sander, Bjoern"],["dc.contributor.author","Kastner, Berthold"],["dc.contributor.author","Deckert, Jochen"],["dc.contributor.author","Dube, Prakash"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Stark, Holger"],["dc.contributor.author","Lührmann, Reinhard"],["dc.date.accessioned","2021-03-05T08:58:33Z"],["dc.date.available","2021-03-05T08:58:33Z"],["dc.date.issued","2007"],["dc.identifier.doi","10.1038/sj.emboj.7601631"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/80177"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.eissn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.title","Composition and three-dimensional EM structure of double affinity-purified, human prespliceosomal A complexes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2422"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","Genes & Development"],["dc.bibliographiccitation.lastpage","2434"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Mozaffari-Jovin, Sina"],["dc.contributor.author","Santos, Karine F."],["dc.contributor.author","Hsiao, He-Hsuan"],["dc.contributor.author","Will, Cindy L."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Wahl, Markus C."],["dc.contributor.author","Luehrmann, Reinhard"],["dc.date.accessioned","2018-11-07T09:04:02Z"],["dc.date.available","2018-11-07T09:04:02Z"],["dc.date.issued","2012"],["dc.description.abstract","The spliceosomal RNA helicase Brr2 catalyzes unwinding of the U4/U6 snRNA duplex, an essential step for spliceosome catalytic activation. Brr2 is regulated in part by the spliceosomal Prp8 protein by an unknown mechanism. We demonstrate that the RNase H (RH) domain of yeast Prp8 binds U4/U6 small nuclear RNA (snRNA) with the single-stranded regions of U4 and U6 preceding U4/U6 stem I, contributing to its binding. Via cross-linking coupled with mass spectrometry, we identify RH domain residues that contact the U4/U6 snRNA. We further demonstrate that the same single-stranded region of U4 preceding U4/U6 stem I is recognized by Brr2, indicating that it translocates along U4 and first unwinds stem I of the U4/U6 duplex. Finally, we show that the RH domain of Prp8 interferes with U4/U6 unwinding by blocking Brr2's interaction with the U4 snRNA. Our data reveal a novel mechanism whereby Prp8 negatively regulates Brr2 and potentially prevents premature U4/U6 unwinding during splicing. They also support the idea that the RH domain acts as a platform for the exchange of U6 snRNA for U1 at the 59 splice site. Our results provide insights into the mechanism whereby Brr2 unwinds U4/U6 and show how this activity is potentially regulated prior to spliceosome activation."],["dc.identifier.doi","10.1101/gad.200949.112"],["dc.identifier.isi","000310583900007"],["dc.identifier.pmid","23124066"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/25022"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cold Spring Harbor Lab Press, Publications Dept"],["dc.relation.issn","0890-9369"],["dc.title","The Prp8 RNase H-like domain inhibits Brr2-mediated U4/U6 snRNA unwinding by blocking Brr2 loading onto the U4 snRNA"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]