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This is an old revision of this page, as edited by ExasperatedOctopus (talk | contribs) at 23:06, 16 November 2020 (Added a bunch of information, will organize later). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Sources for the article Decapping Complex: This is a review[1], This is a review[2], This is primary source about a specific protein in the complex[3], This is one of the first articles discussing the degredation of mRNA and decapping complexes published on Pubmed[4]


Organization ideas, likely to be scattered about the current, existing Decapping Complex:

Structure of the complex

The various subunits are called slightly different things depending on the organism they come from. [1]

This is what is currently written, anything italicized is not mine. But I've linked some things that were previously unlinked, and noted some things that I'm considering changing:

Yeast decapping complex

In yeast (S. cerevisiae), Dcp2 is joined by the decapping activator Dcp1, the helicase Dhh1, the exonuclease Xrn1, nonsense mediated decay factors Upf1, Upf2, and Upf3, the LSm complex, Pat1, and various other proteins. These proteins all localize to cytoplasmic structures called P-bodies. Notably in yeast there are no translation factors or ribosomal proteins inside P-bodies.

Metazoan decapping complex

Higher eukaryotes have slightly different members of the decapping complex. The enzyme Dcp2 is the main catalytic subunit, which forms a holoenzyme with Dcp1, and interacts with auxillary proteins such as Xrn1, Upf1, Upf2, Upf3, PNRC2, the LSm complex, and the Dhh1 ortholog Rck/p-54 to properly carry out its function.[3][2][1] Proteins unique to plants and mammals include the beta propeller protein Hedls and the enhancer of decapping Edc3. Structural details of the assembly of this complex are not known, only physical association by immunoprecipitation.

Dcp2, as the main catalyst of the reaction, relies on a specific pattern of amino acids called a nudix domain to align itself with the 5' cap in order to hydrolize it.[1] A nudix domain is made by packing two beta sheets between multiple alpha helices, can be various lengths and sizes, and is generally used by proteins to identify other structures to interact with them.[5] In the case of Dcp2, it contains multiple glutamate side chains that are negatively charged in normal cellular conditions, and these are what allow the protein to manipulate water molecules to hydrolize the tri-phosphate bridge that connects the 5' end of the mRNA to the 7-methylguanosine cap. Therefore, the nudix domain is what allows Dcp2 to start interacting with the 5' cap. In front of the nudix domain is an N-terminal regulatory domain (NRD), which helps hydrolize the 5' mRNA cap, and a C-terminal area called Box B helps bind the protein to RNA. [1] With all three of these main motifs, Dcp2 is able to find, bind firmly to, and hydrolize a 5' mRNA cap. It does this by recognizing a hairpin loop in the RNA within 10 base pairs of the cap, which is called a Dcp2 binding and decapping element, or by a separate protein recognizing a base pair pattern in the mRNA and directly recruting the holoenzyme.[2] Unfortunately, Dcp2 works slowly, and needs a few other proteins to coordinate with it to decap mRNA in a timely manner.

Dcp1 is a regulatory subunit, it combines with Dcp2, creating a holoenzyme that can decap mRNA properly.[6] Without Dcp1, it is actually impossible for Dcp2 to decap anything in vivo, and it only works incredibly slowly in vitro, which makes forming this holoenzyme an essential process.[1] Its secondary structure consistes of seven beta sheets and three alpha helices. which come together to form a v-shaped tertiary structure. The defining features of Dcp1 are the EVH1 domain and a domain that recognises proline rich sequence (PRS). The EVH1 domain interacts directly with the NRD of Dcp2, and is currently though to directly help with the decapping of mRNA, though how it does so is currently unclear. The domain that recognises PRS is within the cleft of the 'V' of the protein, and binds PNRC2's proline-rich region, which the further regulates Dcp2. [6]

PNRC2 enhances the effect of Dcp1 to encourage decapping, and also recruits Upf1 to the decapping complex. Current research suggests PNRC2 helps associate Dcp2 and Dcp1 together, therefore increasing the effectiveness of Dcp2, but the exact details about how it does so are vague.[7] The recruitment of Upf1 allows the decapping complex to participate in nonsense-mediated mRNA decay, which makes PNRC2 a way for Dcp2 to connect with the regulatory pathway in charge of destroying incorrectly transcripted mRNA.[8]

Upf1-3 are proteins involved in the regulatory pathway of nonsense-mediated mRNA decay, and not the actual decapping of mRNA. They are activators of the complex, in that they can direct the complex at incorrectly formed mRNA.[2]

Edc3 further activates the holoenzyme Dcp2-Dcp1 and allows it to actually decap mRNA. It possesses an LSm domain at the N-terminal, which interacts with HLM fragments on the C terminal of Dcp1 and allows for Edc3 to bind to it, therefore an FDF linker, which is a long and unstructured stretch of amino acids that affects Dhh1's ability to bind with mRNA, and an Yjef-N C-terminus domain which dimerizes with mRNA and helps create P-bodies.[1] P bodies are essentially stockpiled clumps of decapped or repressed RNA mixed together with RNA degredation factors, so they are important for the eventual destruction of the mRNA altered by Dcp2.

Dhh1 stimulates mRNA decapping as well. It is proposed that, since it is a helicase, it is involved in reconfiguring the 5' end of the mRNA to give easier access to Dcp2 and all it's constituents, and that it stimulates Dcp1 so that it interacts better with Dcp2.[9]

Pat1 is another activator for the decapping complex. [10] It has three main domains, one of which is necessary for decapping mRNA, and the other two make it easier for the protein to activate decapping.[11]The N-terminal domain interacts with Dhh1 and brings it close so it can activate Dcp1, another part helps create P-bodies, and the middle and C-terminal domains make Dcp1–Dcp2, the Lsm1–7 complex and Xrn1 join the complex. Pat1 has many interactions with the various proteins in the decapping complex, and is therefore known as the 'scaffolding protein' because it brings everything together when it is time to decap something.[1][12]

Xrn1 mediates the degredation of the just-decapped mRNA, since it targets the 5' monophosphate end of mRNA, which is what is left over when Dcp2 has hydrolized the cap. The current theory is that the structure of Xrn1 does not allow a capped mRNA to interact with it because there is steric hindrance that physically blocks the protein from interacting with anything RNA that Dcp2 has not already altered.[3]


How the Complex Decaps mRNA

Dcp2 is the protein that actually decaps mRNA, and the rest of proteins in the complex enhance it's funtion and allow it to hydrolyze the mRNA 5' cap.[1]

Why Decapping mRNA is Important (?)-The fact is that mRNA needs to be degraded at some point, or else mRNA will keep floating around the cell and create unwanted proteins at random. The mRNA 5' cap is specifically designed to keep mRNA from being degraded before it can be used, and so needs to be removed from the mRNA so the mRNA decay pathway can take care of it.[4]

  1. ^ a b c d e f g h i Charenton, Clément; Graille, Marc (2018-12-19). "mRNA decapping: finding the right structures". Philosophical Transactions of the Royal Society B: Biological Sciences. 373 (1762): 20180164. doi:10.1098/rstb.2018.0164. PMC 6232594. PMID 30397101.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c d Kramer, Susanne; McLennan, Alexander G. (2019). "The complex enzymology of mRNA decapping: Enzymes of four classes cleave pyrophosphate bonds". WIREs RNA. 10 (1): e1511. doi:10.1002/wrna.1511. ISSN 1757-7012.
  3. ^ a b c Delorme-Axford, Elizabeth; Abernathy, Emma; Lennemann, Nicholas J.; Bernard, Amélie; Ariosa, Aileen; Coyne, Carolyn B.; Kirkegaard, Karla; Klionsky, Daniel J. (2018-05-04). "The exoribonuclease Xrn1 is a post-transcriptional negative regulator of autophagy". Autophagy. 14 (5): 898–912. doi:10.1080/15548627.2018.1441648. ISSN 1554-8627. PMC 6070002. PMID 29465287.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ a b Beelman, C. A.; Parker, R. (1995-04-21). "Degradation of mRNA in eukaryotes". Cell. 81 (2): 179–183. doi:10.1016/0092-8674(95)90326-7. ISSN 0092-8674. PMID 7736570.
  5. ^ "InterPro". www.ebi.ac.uk. Retrieved 2020-11-14.
  6. ^ a b She, Meipei; Decker, Carolyn J; Sundramurthy, Kumar; Liu, Yuying; Chen, Nan; Parker, Roy; Song, Haiwei (2004-3). "Crystal structure of Dcp1p and its functional implications in mRNA decapping". Nature structural & molecular biology. 11 (3): 249–256. doi:10.1038/nsmb730. ISSN 1545-9993. PMC 2040073. PMID 14758354. {{cite journal}}: Check date values in: |date= (help)
  7. ^ "Structural Basis of the PNRC2-Mediated Link between mRNA Surveillance and Decapping". Structure. 20 (12): 2025–2037. 2012-12-05. doi:10.1016/j.str.2012.09.009. ISSN 0969-2126.
  8. ^ Baker, Kristian E; Parker, Roy (2004-06-01). "Nonsense-mediated mRNA decay: terminating erroneous gene expression". Current Opinion in Cell Biology. 16 (3): 293–299. doi:10.1016/j.ceb.2004.03.003. ISSN 0955-0674.
  9. ^ Fischer, Nicole; Weis, Karsten (2002-06-03). "The DEAD box protein Dhh1 stimulates the decapping enzyme Dcp1". The EMBO Journal. 21 (11): 2788–2797. doi:10.1093/emboj/21.11.2788. ISSN 0261-4189. PMID 12032091.
  10. ^ Franks, Tobias M.; Lykke-Andersen, Jens (2008-12-05). "The Control of mRNA Decapping and P-Body Formation". Molecular cell. 32 (5): 605–615. doi:10.1016/j.molcel.2008.11.001. ISSN 1097-2765. PMC 2630519. PMID 19061636.
  11. ^ Pilkington, Guy R.; Parker, Roy (2008-02-15). "Pat1 Contains Distinct Functional Domains That Promote P-Body Assembly and Activation of Decapping". Molecular and Cellular Biology. 28 (4): 1298–1312. doi:10.1128/MCB.00936-07. ISSN 0270-7306. PMID 18086885.
  12. ^ Sharif, Humayun; Ozgur, Sevim; Sharma, Kundan; Basquin, Claire; Urlaub, Henning; Conti, Elena (2013-9). "Structural analysis of the yeast Dhh1–Pat1 complex reveals how Dhh1 engages Pat1, Edc3 and RNA in mutually exclusive interactions". Nucleic Acids Research. 41 (17): 8377–8390. doi:10.1093/nar/gkt600. ISSN 0305-1048. PMC 3783180. PMID 23851565. {{cite journal}}: Check date values in: |date= (help)
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