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Structural and functional insights into eukaryotic mRNA decapping

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Abstract The control of messenger RNA (mRNA) translation and degradation is important in regulation of eukaryotic gene expression. In the general and specialized mRNA decay pathways which involve 5′→3′ decay, decapping is the central step because it is the controlling gate preceding the actual degradation of mRNA and is a site of numerous control inputs. Removal of the cap structure is catalyzed by a decapping holoenzyme composed of the catalytic Dcp2 subunit and the coactivator Dcp1. Decapping is regulated by decapping activators and inhibitors. Recent structural and kinetics studies indicated that Dcp1 and the substrate RNA promote the closed form of the enzyme and the catalytic step of decapping is rate limiting and accelerated by Dcp1. The conformational change between the open and closed decapping enzyme is important for controlling decapping, and regulation of this transition has been proposed to be a checkpoint for determining the fate of mRNAs. Here we summarize the past and recent advances on the structural and functional studies of protein factors involved in regulating mRNA decapping. WIREs RNA 2011 2 193–208 DOI: 10.1002/wrna.44 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

The crystal structures of Dcp1 and Dcp2 proteins. (a) A schematic diagram depicting the domain organization of Dcp1 and Dcp2 proteins. Only metazoan Dcp1 possess the C‐terminal trimerization domain. (b) The ribbon diagram of the C‐terminally truncated Schizosaccharomyces pombe Dcp2 protein structure (residues 1–266). (c) The ribbon diagram of the Saccharomyces cerevisiae Dcp1 protein structure. (d) The ribbon diagram of the closed form of the C‐terminally truncated SpDcp2 protein (residues 1–266) in complex with ScDcp1 protein. (e) The ribbon diagram of the open form of the C‐terminally truncated SpDcp2 protein (residues 1–266) in complex with ScDcp1 protein. The EVH1 domain of ScDcp1 is highlighted in green color. For SpDcp2, the N‐terminal domain (Dcp2NTD) is highlighted in pink and the Nudix domain is in blue with the catalytic Nudix motif in red. The coloring scheme are the same for (a)–(e). Bound nucleotide, ATP is shown in stick model.

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A schematic diagram comparing (1) uridylation‐ and (2) deadenylation‐dependent decapping, and (3) deadenylation‐independent decapping of messenger RNAs which lead to 5→3 decay.

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Messenger RNA (mRNA)‐specific decapping activation pathways. (a) In nonsense‐mediated decay (NMD) (1) the hyperphosphorylated Upf1 of the NMD survelliance complex (2) associates directly with proline‐rich nuclear receptor coregulatory 2, which is a recently identified protein crucial for bridging Upf1 and (3) Dcp1a, thus linking mRNA surveillance to decapping. (b) In AU‐rich element (ARE)‐mediated decay (1) tristetrapolin binds to AREs on the 3 untranslated region (UTR) of ARE‐rich mRNAs and (2) interacts with Edc3 (3) recruiting the decapping enzyme and other decapping proteins, leading to removal of the 5 cap. (c) In microRNA (miRNA)‐mediated decay (1) miRNA and associated Argonaute proteins (2) recruiting the decapping enzyme Dcp1–Dcp2 and the rest of the decapping proteins (3) leading to removal of the 5 cap by decapping. (d) In Rps28b‐mediated decay (1) in the autoregulatory system of Rps28b, Rps28b ribosomal protein binds to a conserved hairpin loop formed at the 3 UTR of its mRNA. Edc3 binds to Rps28b and (2) recruits the decapping enzyme Dcp1–Dcp2 and other decapping proteins (3) leading to the removal of the 5 cap.

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A schematic diagram illustrating the Lsm1‐7 complex inhibition of 3→5 decay and decapping activation leading to 5→3 decay.

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A schematic diagram depicting the domain organization of decapping activators and their interactions with each other. Dcp1: EVH1 domain, green color; trimerization domain, gray color. Dcp2: N‐terminal domain, pink color; Nudix domain, blue color; Nudix motif, red color. Dhh1: helicase domain, orange color. Pat1: light blue color. Edc3: red color. Lsm1‐7 complex: yellow color. Hedls: WD repeats, black color; Q/N domain, purple color. Solid lines indicate strong binding and dashed lines indicate weak binding.

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A simple model diagram depicting translational repression and decapping activation of messenger RNA (mRNA). Translationally active mRNA becomes translationally repressed in an unknown mechanism that involves translation repressors Dhh1 and Pat1 which inhibits translation. Additional decapping activators such as Edc3 and the Lsm1–7 complex bind to the translationally repressed complex, stimulating the decapping enzyme Dcp1–Dcp2, and this leads to decapping and subsequently mRNA decay.

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Regulation of mRNA decapping

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