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The structural landscape of native editosomes in African trypanosomes

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Abstract The majority of mitochondrial pre‐messenger RNAs in African trypanosomes are substrates of a U‐nucleotide‐specific insertion/deletion‐type RNA editing reaction. The process converts nonfunctional pre‐mRNAs into translation‐competent molecules and can generate protein diversity by alternative editing. High molecular mass protein complexes termed editosomes catalyze the processing reaction. They stably interact with pre‐edited mRNAs and small noncoding RNAs, known as guide RNAs (gRNAs), which act as templates in the reaction. Editosomes provide a molecular surface for the individual steps of the catalytic reaction cycle and although the protein inventory of the complexes has been studied in detail, a structural analysis of the processing machinery has only recently been accomplished. Electron microscopy in combination with single particle reconstruction techniques has shown that steady state isolates of editosomes contain ensembles of two classes of stable complexes with calculated apparent hydrodynamic sizes of 20S and 35–40S. 20S editosomes are free of substrate RNAs, whereas 35–40S editosomes are associated with endogenous mRNA and gRNA molecules. Both complexes are characterized by a diverse structural landscape, which include complexes that lack or possess defined subdomains. Here, we summarize the consensus models and structural landmarks of both complexes. We correlate structural features with functional characteristics and provide an outlook into dynamic aspects of the editing reaction cycle. WIREs RNA 2011 2 395–407 DOI: 10.1002/wrna.67 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Processing > RNA Editing and Modification

Integration of the consensus 20S structure into an outline (red) of the consensus 35–40S complex. The two nearly globular 20S subdomains are labeled SD1 and SD2. IR marks the interface region that connects subdomain 1 with subdomain 2. The semispherical back (SB) is in contact with both subdomains and reaches into the interface region. The semispherical element consists of bound substrate RNA.

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Structural landscape of the Trypanosoma brucei 20S editosome.37 (a) Refined models of four representative 3D class averages. (b) Shape profiling of the 20S complex by color‐scale encoded overlays. The data demonstrate that the majority of complexes are composed of two subdomains connected by a broad interface (red).

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Consensus structure of the Trypanosoma brucei 20S RNA editing complex.37 (a) Raw electron microscopy images of five individual complexes in different orientations. (b) Model of the consensus structure of the 20S complex. Four shaded surface views are shown rotated clockwise in 90° increments along the vertical axis. Prominent structural landmarks are labeled in (c).

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Structural landscape of the Trypanosoma brucei 35–40S editosome.37 (a) Refined models of six representative 3D class averages. (b) Shape profiling of the 35–40S complex by color‐scale encoded overlays. The data demonstrate that the majority of complexes consist of a platform density that converges in a semispherical back element (red).

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Consensus structure of the Trypanosoma brucei 35–40S RNA editing complex.37 (a) Raw electron microscopy images of five individual complexes in different orientations. (b) Model of the consensus structure of the 35–40S complex. Four shaded surface views are shown rotated clockwise in 90° increments along the vertical axis. Prominent structural landmarks are labeled in (c).

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Cartoon of an editosome/substrate RNA interaction. Annealed guide RNA (blue)/pre‐mRNA (black) hybrid molecules bind into the substrate binding pocket of the editosome by adopting a three‐helix junction geometry. Ribonucleotide positions to be edited (3 Us in red) are oriented toward the catalytic center of the complex. Editosomes exhibit a polyfunctional active site, which contains all enzyme activities to catalyze both, U‐insertions and U‐deletions. In its most basic form this includes endonuclease (N), TUTase (T), exoUase (X), RNA ligase (L), and RNA helicase (H) activities. In addition, nucleoside triphosphate (ATP, UTP) binding and hydrolysis functions have been identified.

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Molecular ensembles of active editosomes. 20S editosomes interact with a large intracellular pool of substrate RNAs (blue ribbons) with different molecular masses and folding characteristics and as a consequence with different hydrodynamic radii. This results in a sizeable structural landscape of RNA‐bound editosomes, which differ for the most part in the dimension of the semispherical back element. The binding of ‘large’ substrate RNAs generates 35–40S editosomes, whereas the binding of ‘small’ RNA ligands results in RNA‐loaded editosomes with S‐values only marginally above 20S.

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RNA Processing > RNA Editing and Modification
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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