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https://www.readbyqxmd.com/read/28088760/usp15-regulates-dynamic-protein-protein-interactions-of-the-spliceosome-through-deubiquitination-of-prp31
#1
Tanuza Das, Joon Kyu Park, Jinyoung Park, Eunji Kim, Michael Rape, Eunice EunKyeong Kim, Eun Joo Song
Post-translational modifications contribute to the spliceosome dynamics by facilitating the physical rearrangements of the spliceosome. Here, we report USP15, a deubiquitinating enzyme, as a regulator of protein-protein interactions for the spliceosome dynamics. We show that PRP31, a component of U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and deubiquitinated by USP15 and its substrate targeting factor SART3. USP15(SART3) makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3...
January 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28076346/cryo-em-structure-of-a-human-spliceosome-activated-for-step-2-of-splicing
#2
Karl Bertram, Dmitry E Agafonov, Wen-Ti Liu, Olexandr Dybkov, Cindy L Will, Klaus Hartmuth, Henning Urlaub, Berthold Kastner, Holger Stark, Reinhard Lu Hrmann
Spliceosome rearrangements facilitated by RNA helicase Prp16 before catalytic step 2 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 RNP core of the human C* spliceosome is highly similar to that of the yeast pre-Prp16 C complex. However, in C* the branched intron region is separated (by ~20 Å) from the catalytic centre, and its position close to the U6 snRNA ACAGA box is stabilised by interactions with the Prp8 RNase H-like and Prp17 WD40 domains...
January 11, 2017: Nature
https://www.readbyqxmd.com/read/28076345/structure-of-a-spliceosome-remodelled-for-exon-ligation
#3
Sebastian M Fica, Chris Oubridge, Wojciech P Galej, Max E Wilkinson, Xiao-Chen Bai, Andrew J Newman, Kiyoshi Nagai
The spliceosome excises introns from pre-mRNAs in two sequential trans-esterifications - branching and exon ligation(1) - catalysed at a single catalytic metal site in U6 snRNA(2,3). The recent structures of the spliceosomal C complex(4,5) with the cleaved 5'-exon and lariat-3'-exon bound to the catalytic centre revealed that branching-specific factors such as Cwc25 lock the branch helix into position for nucleophilic attack of the branch adenosine at the 5'-splice site. Furthermore, the ATPase Prp16 is positioned to bind and translocate the intron downstream of the branch point to destabilize branching-specific factors and release the branch helix from the active site(4)...
January 11, 2017: Nature
https://www.readbyqxmd.com/read/28053119/short-intron-derived-ncrnas
#4
Florent Hubé, Damien Ulveling, Alain Sureau, Sabrina Forveille, Claire Francastel
Introns represent almost half of the human genome, although they are eliminated from transcripts through RNA splicing. Yet, different classes of non-canonical miRNAs have been proposed to originate directly from intron splicing. Here, we considered the alternative splicing of introns as an interesting source of miRNAs, compatible with a developmental switch. We report computational prediction of new Short Intron-Derived ncRNAs (SID), defined as precursors of smaller ncRNAs like miRNAs and snoRNAs produced directly by splicing, and tested their dependence on each key factor in canonical or alternative miRNAs biogenesis (Drosha, DGCR8, DBR1, snRNP70, U2AF65, PRP8, Dicer, Ago2)...
January 3, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27980089/structure-of-a-yeast-step-ii-catalytically-activated-spliceosome
#5
Chuangye Yan, Ruixue Wan, Rui Bai, Gaoxingyu Huang, Yigong Shi
Each cycle of pre-mRNA splicing comprises two sequential reactions, first freeing the 5'-exon and generating an intron lariat-3'-exon, and then ligating the two exons and releasing the intron lariat. The second reaction is executed by the step II catalytically activated spliceosome (known as the C* complex). Here, we present the cryo-electron microscopy (cryo-EM) structure of a C* complex from Saccharomyces cerevisiae at an average resolution of 4.0 Å. Compared with the preceding spliceosomal complex (C complex), the lariat junction has been translocated by 15 to 20 Å to vacate space for the incoming 3'-exon sequences...
December 15, 2016: Science
https://www.readbyqxmd.com/read/27880071/interplay-of-cis-and-trans-regulatory-mechanisms-in-the-spliceosomal-rna-helicase-brr2
#6
Eva Absmeier, Christian Becke, Jan Wollenhaupt, Karine F Santos, Markus C Wahl
RNA helicase Brr2 is implicated in multiple phases of pre-mRNA splicing and thus requires tight regulation. Brr2 can be auto-inhibited via a large N-terminal region folding back onto its helicase core and auto-activated by a catalytically inactive C-terminal helicase cassette. Furthermore, it can be regulated in trans by the Jab1 domain of the Prp8 protein, which can inhibit Brr2 by intermittently inserting a C-terminal tail in the enzyme's RNA-binding tunnel or activate the helicase after removal of this tail...
January 2, 2017: Cell Cycle
https://www.readbyqxmd.com/read/27792457/functions-and-regulation-of-the-brr2-rna-helicase-during-splicing
#7
Eva Absmeier, Karine F Santos, Markus C Wahl
Pre-mRNA splicing entails the stepwise assembly of an inactive spliceosome, its catalytic activation, splicing catalysis and spliceosome disassembly. Transitions in this reaction cycle are accompanied by compositional and conformational rearrangements of the underlying RNA-protein interaction networks, which are driven and controlled by 8 conserved superfamily 2 RNA helicases. The Ski2-like helicase, Brr2, provides the key remodeling activity during spliceosome activation and is additionally implicated in the catalytic and disassembly phases of splicing, indicating that Brr2 needs to be tightly regulated during splicing...
December 16, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27760804/the-reverse-transcriptase-rna-maturase-protein-matr-is-required-for-the-splicing-of-various-group-ii-introns-in-brassicaceae-mitochondria
#8
Laure D Sultan, Daria Mileshina, Felix Grewe, Katarzyna Rolle, Sivan Abudraham, Paweł Głodowicz, Adnan Khan Niazi, Ido Keren, Sofia Shevtsov, Liron Klipcan, Jan Barciszewski, Jeffrey P Mower, André Dietrich, Oren Ostersetzer-Biran
Group II introns are large catalytic RNAs that are ancestrally related to nuclear spliceosomal introns. Sequences corresponding to group II RNAs are found in many prokaryotes and are particularly prevalent within plants organellar genomes. Proteins encoded within the introns themselves (maturases) facilitate the splicing of their own host pre-RNAs. Mitochondrial introns in plants have diverged considerably in sequence and have lost their maturases. In angiosperms, only a single maturase has been retained in the mitochondrial DNA: the matR gene found within NADH dehydrogenase 1 (nad1) intron 4...
November 2016: Plant Cell
https://www.readbyqxmd.com/read/27562955/molecular-architecture-of-the-saccharomyces-cerevisiae-activated-spliceosome
#9
Reinhard Rauhut, Patrizia Fabrizio, Olexandr Dybkov, Klaus Hartmuth, Vladimir Pena, Ashwin Chari, Vinay Kumar, Chung-Tien Lee, Henning Urlaub, Berthold Kastner, Holger Stark, Reinhard Lührmann
The activated spliceosome (B(act)) is in a catalytically inactive state and is remodeled into a catalytically active machine by the RNA helicase Prp2, but the mechanism is unclear. Here, we describe a 3D electron cryomicroscopy structure of the Saccharomyces cerevisiae B(act) complex at 5.8-angstrom resolution. Our model reveals that in B(act), the catalytic U2/U6 RNA-Prp8 ribonucleoprotein core is already established, and the 5' splice site (ss) is oriented for step 1 catalysis but occluded by protein. The first-step nucleophile-the branchsite adenosine-is sequestered within the Hsh155 HEAT domain and is held 50 angstroms away from the 5'ss...
September 23, 2016: Science
https://www.readbyqxmd.com/read/27459055/cryo-em-structure-of-the-spliceosome-immediately-after-branching
#10
Wojciech P Galej, Max E Wilkinson, Sebastian M Fica, Chris Oubridge, Andrew J Newman, Kiyoshi Nagai
Precursor mRNA (pre-mRNA) splicing proceeds by two consecutive transesterification reactions via a lariat-intron intermediate. Here we present the 3.8 Å cryo-electron microscopy structure of the spliceosome immediately after lariat formation. The 5'-splice site is cleaved but remains close to the catalytic Mg(2+) site in the U2/U6 small nuclear RNA (snRNA) triplex, and the 5'-phosphate of the intron nucleotide G(+1) is linked to the branch adenosine 2'OH. The 5'-exon is held between the Prp8 amino-terminal and linker domains, and base-pairs with U5 snRNA loop 1...
September 8, 2016: Nature
https://www.readbyqxmd.com/read/27445308/structure-of-a-yeast-catalytic-step-i-spliceosome-at-3-4-%C3%A3-resolution
#11
Ruixue Wan, Chuangye Yan, Rui Bai, Gaoxingyu Huang, Yigong Shi
Each cycle of pre-messenger RNA splicing, carried out by the spliceosome, comprises two sequential transesterification reactions, which result in the removal of an intron and the joining of two exons. Here we report an atomic structure of a catalytic step I spliceosome (known as the C complex) from Saccharomyces cerevisiae, as determined by cryo-electron microscopy at an average resolution of 3.4 angstroms. In the structure, the 2'-OH of the invariant adenine nucleotide in the branch point sequence (BPS) is covalently joined to the phosphate at the 5' end of the 5' splice site (5'SS), forming an intron lariat...
August 26, 2016: Science
https://www.readbyqxmd.com/read/27445306/structure-of-a-yeast-activated-spliceosome-at-3-5-%C3%A3-resolution
#12
Chuangye Yan, Ruixue Wan, Rui Bai, Gaoxingyu Huang, Yigong Shi
Pre-messenger RNA (pre-mRNA) splicing is carried out by the spliceosome, which undergoes an intricate assembly and activation process. Here, we report an atomic structure of an activated spliceosome (known as the B(act) complex) from Saccharomyces cerevisiae, determined by cryo-electron microscopy at an average resolution of 3.52 angstroms. The final refined model contains U2 and U5 small nuclear ribonucleoprotein particles (snRNPs), U6 small nuclear RNA (snRNA), nineteen complex (NTC), NTC-related (NTR) protein, and a 71-nucleotide pre-mRNA molecule, which amount to 13,505 amino acids from 38 proteins and a combined molecular mass of about 1...
August 26, 2016: Science
https://www.readbyqxmd.com/read/27368340/a-protein-map-of-the-yeast-activated-spliceosome-as-obtained-by-electron-microscopy
#13
Chengfu Sun, Norbert Rigo, Patrizia Fabrizio, Berthold Kastner, Reinhard Lührmann
We have elucidated the spatial arrangement of proteins and snRNP subunits within the purified spliceosomal B(act) complex from Saccharomyces cerevisiae, using negative-stain immunoelectron microscopy. The B(act) spliceosome exhibits a mushroom-like shape with a main body connected to a foot and a steep and a shallow slope. The U5 core components, including proteins Snu114 and Prp8, are located in the main body and foot, while Brr2 is on the shallow slope. U2 snRNP components and the RNA helicase Prp2 were predominantly located in the upper regions of both slopes...
September 2016: RNA
https://www.readbyqxmd.com/read/27354531/substrate-assisted-mechanism-of-rnp-disruption-by-the-spliceosomal-brr2-rna-helicase
#14
Matthias Theuser, Claudia Höbartner, Markus C Wahl, Karine F Santos
The Brr2 RNA helicase disrupts the U4/U6 di-small nuclear RNA-protein complex (di-snRNP) during spliceosome activation via ATP-driven translocation on the U4 snRNA strand. However, it is unclear how bound proteins influence U4/U6 unwinding, which regions of the U4/U6 duplex the helicase actively unwinds, and whether U4/U6 components are released as individual molecules or as subcomplexes. Here, we set up a recombinant Brr2-mediated U4/U6 di-snRNP disruption system, showing that sequential addition of the U4/U6 proteins small nuclear ribonucleoprotein-associated protein 1 (Snu13), pre-mRNA processing factor 31 (Prp31), and Prp3 to U4/U6 di-snRNA leads to a stepwise decrease of Brr2-mediated U4/U6 unwinding, but that unwinding is largely restored by a Brr2 cofactor, the C-terminal Jab1/MPN domain of the Prp8 protein...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27136328/crystal-structures-of-a-group-ii-intron-maturase-reveal-a-missing-link-in-spliceosome-evolution
#15
Chen Zhao, Anna Marie Pyle
Group II introns are self-splicing ribozymes that are essential in many organisms, and they have been hypothesized to share a common evolutionary ancestor with the spliceosome. Although structural similarity of RNA components supports this connection, it is of interest to determine whether associated protein factors also share an evolutionary heritage. Here we present the crystal structures of reverse transcriptase (RT) domains from two group II intron-encoded proteins (maturases) from Roseburia intestinalis and Eubacterium rectale, obtained at 1...
June 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27136327/structure-of-a-group-ii-intron-in-complex-with-its-reverse-transcriptase
#16
Guosheng Qu, Prem Singh Kaushal, Jia Wang, Hideki Shigematsu, Carol Lyn Piazza, Rajendra Kumar Agrawal, Marlene Belfort, Hong-Wei Wang
Bacterial group II introns are large catalytic RNAs related to nuclear spliceosomal introns and eukaryotic retrotransposons. They self-splice, yielding mature RNA, and integrate into DNA as retroelements. A fully active group II intron forms a ribonucleoprotein complex comprising the intron ribozyme and an intron-encoded protein that performs multiple activities including reverse transcription, in which intron RNA is copied into the DNA target. Here we report cryo-EM structures of an endogenously spliced Lactococcus lactis group IIA intron in its ribonucleoprotein complex form at 3...
June 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27114555/recruitment-of-the-nineteen-complex-to-the-activated-spliceosome-requires-atprmt5
#17
Xian Deng, Tiancong Lu, Lulu Wang, Lianfeng Gu, Jing Sun, Xiangfeng Kong, Chunyan Liu, Xiaofeng Cao
Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is involved in a multitude of biological processes in eukaryotes. Symmetric arginine dimethylation mediated by PRMT5 modulates constitutive and alternative pre-mRNA splicing of diverse genes to regulate normal growth and development in multiple species; however, the underlying molecular mechanism remains largely unknown. A genetic screen for suppressors of an Arabidopsis symmetric arginine dimethyltransferase mutant, atprmt5, identified two gain-of-function alleles of pre-mRNA processing factor 8 gene (prp8-8 and prp8-9), the highly conserved core component of the U5 small nuclear ribonucleoprotein (snRNP) and the spliceosome...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27072132/retinitis-pigmentosa-mutations-in-bad-response-to-refrigeration-2-brr2-impair-atpase-and-helicase-activity
#18
Sarah Ledoux, Christine Guthrie
Brr2 is an RNA-dependent ATPase required to unwind the U4/U6 snRNA duplex during spliceosome assembly. Mutations within the ratchet helix of the Brr2 RNA binding channel result in a form of degenerative human blindness known as retinitis pigmentosa (RP). The biochemical consequences of these mutations on Brr2's RNA binding, helicase, and ATPase activity have not yet been characterized. Therefore, we identified the largest construct of Brr2 that is soluble in vitro, which truncates the first 247 amino acids of the N terminus (Δ247-Brr2), to characterize the effects of the RP mutations on Brr2 activity...
June 3, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27058959/fgprp4-kinase-is-important-for-spliceosome-b-complex-activation-and-splicing-efficiency-in-fusarium-graminearum
#19
Xuli Gao, Qiaojun Jin, Cong Jiang, Yang Li, Chaohui Li, Huiquan Liu, Zhensheng Kang, Jin-Rong Xu
PRP4 encodes the only kinase among the spliceosome components. Although it is an essential gene in the fission yeast and other eukaryotic organisms, the Fgprp4 mutant was viable in the wheat scab fungus Fusarium graminearum. Deletion of FgPRP4 did not block intron splicing but affected intron splicing efficiency in over 60% of the F. graminearum genes. The Fgprp4 mutant had severe growth defects and produced spontaneous suppressors that were recovered in growth rate. Suppressor mutations were identified in the PRP6, PRP31, BRR2, and PRP8 orthologs in nine suppressor strains by sequencing analysis with candidate tri-snRNP component genes...
April 2016: PLoS Genetics
https://www.readbyqxmd.com/read/26968627/prp8-retinitis-pigmentosa-mutants-cause-defects-in-the-transition-between-the-catalytic-steps-of-splicing
#20
Megan Mayerle, Christine Guthrie
Pre-mRNA splicing must occur with high fidelity and efficiency for proper gene expression. The spliceosome uses DExD/H box helicases to promote on-pathway interactions while simultaneously minimizing errors. Prp8 and Snu114, an EF2-like GTPase, regulate the activity of the Brr2 helicase, promoting RNA unwinding by Brr2 at appropriate points in the splicing cycle and repressing it at others. Mutations linked to retinitis pigmentosa (RP), a disease that causes blindness in humans, map to the Brr2 regulatory region of Prp8...
May 2016: RNA
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