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Retroelement origins of pre‐mRNA splicing

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Abstract Recent cryo‐EM structures of a group II intron caught in the process of invading DNA have given new insight into the mechanisms of both splicing and retrotransposition. Conformational dynamics involving the branch‐site helix domain VI are responsible for substrate exchange between the two steps of splicing. These structural rearrangements have strong parallels with the movement of the branch‐site helix in the spliceosome during catalysis. This is strong evidence for the spliceosome evolving from a group II intron ancestor. We observe other topological changes in the overall structure of the catalytic domain V that may occur in the spliceosome as well. Therefore, studying group II introns not only provides us with insight into the evolutionary origins of the spliceosome, but also may inform the design of experiments to further probe structure–function relationships in this eukaryotic splicing apparatus. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution
Representative secondary structure of a group II intron. Group II introns have a conserved secondary structure with six domains labeled with Roman numerals I–VI. The exon binding sequences (EBS 1–3) are used to recognize the 5′ and 3′ splice sites (SS) by Watson‐Crick pairing to the intron binding sequences (IBS 1–3). Relevant tertiary interactions are labeled with Greek symbols
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The retroelement origin of the spliceosome. During the endosymbiont event, a eubacterium is hypothesized to have been phagocytosed by an archaebacterium. Once engulfed, the archaebacterium began to digest the eubacteria, leading to a partial degradation of the eubacterial membrane. This allowed group II introns to escape from the eubacterium and invade the genome of the archaebacterium. The sudden addition of group II introns within coding regions of the archaebacterial genome led to a selective pressure to decouple transcription from translation. The evolutionary solution to this problem was the formation of the nuclear membrane. Meanwhile, group II introns began to degenerate becoming less active as retroelements. This degeneration continued as the group II intron became fragmented, eventually forming the modern‐day spliceosome
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The dynamics of RNA splicing are conserved. In both the group II intron (PDB 6ME0 and 6MEC) and the spliceosome (PDB 6QDV and 5LJ5), the mechanism of substrate exchange is conserved. The helix containing the bulged adenosine (DVI in group II introns and the branch helix in the spliceosome) undergo a large 90° swinging motion. This motion helps to remove the lariat bond from the active site during forward splicing, allowing the complex to proceed with the second transesterification reaction
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ψ and φ interactions facilitate DVI dynamics. In the pre‐1r state, four tertiary interactions are engaged (ψ–ψ′, φ–φ′, π–π′, and η–η′). To facilitate the transition to the pre‐2r state, all four of these interactions must disengage. This process likely initiates with the disengagement of ψ–ψ′, which causes structural perturbations that propagate down DV and results in the disruption of φ–φ′, π–π′, and η–η′. Once free, DVI can sample conformational space and is eventually captured by the matX‐DVI and ι–ι′ interactions
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Conservation of sequence and structure between group II introns and the spliceosome. (a) Left. A secondary structure of the core components is shown for the T.el4h group II intron from the cyanobacterium Thermosynechococcus elongatus. The main features that make up the catalytic triplex are shown. Right. The catalytic triplex from PDB 6ME0 is shown in detail. Hydrogen bonds are represented with yellow dashes and the catalytic metal ions (M1 and M2) are shown as orange spheres. (b) The core features of the human spliceosome are conserved when compared to the group II intron. U2 and U6 pair to form the catalytic triplex (PDB 6QDV) with an almost identical tertiary structure
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Replication cycle of a group II intron retroelement. Group II introns are first transcribed from a DNA sequence, after which the open reading frame (ORF) for the maturase protein is translated. The resulting maturase protein then binds to the intron RNA and promotes forward splicing. The products of this process are an excised lariat/maturase complex as well as ligated exons fit for translation. The intron lariat complex is then free to diffuse and bind to dsDNA that contains a sequence that is partially complementary to the EBS found within the RNA. Once bound, the RNA undergoes reverse splicing, which covalently attaches the RNA on both ends to the DNA. The maturase protein then uses its endonuclease (En) domain to cleave the bottom strand of DNA and its reverse transcriptase (RT) domain to synthesize a cDNA copy of the intron RNA. Host repair and recombination pathways complete the insertion of the group II intron copy
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RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry
RNA Processing > Splicing Mechanisms

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