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Decapping complex
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Decapping complex
The mRNA decapping complex is a protein complex in eukaryotic cells responsible for removal of the 5' cap. The active enzyme of the decapping complex is the bilobed Nudix family enzyme Dcp2, which hydrolyzes 5' cap and releases 7mGDP and a 5'-monophosphorylated mRNA. This decapped mRNA is inhibited for translation and will be degraded by exonucleases. The core decapping complex is conserved in eukaryotes. Dcp2 is activated by Decapping Protein 1 (Dcp1) and in higher eukaryotes joined by the scaffold protein VCS. Together with many other accessory proteins, the decapping complex assembles in P-bodies in the cytoplasm.
mRNA needs to be degraded, or else it 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 so the mRNA decay pathway can take care of it.
Dcp2 is the protein that actually decaps mRNA, and the rest of proteins in the complex enhance its function and allow it to hydrolyze the chemical bond attaching the mRNA to the 5' cap. The Nudix domain in Dcp2 hydrolyzes one of the bonds on the triphosphate bridge that hooks the mRNA and the 5' cap together, causing the 7-methylguanosine cap to come off and leaving the mRNA open to degradation by the exonucleases in the cell.
Both single-celled and multicellular organisms need to decap their mRNA to get rid of it, but different organisms have slightly different proteins that carry out this process. There are many proteins that stay the same, but several key differences between the single-celled (yeast) and multicellular (metazoan) decapping complexes.
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.
Higher eukaryotes have slightly different members of the decapping complex. The enzyme Dcp2 is still the catalytic subunit which forms a holoenzyme with Dcp1, and interacts with auxiliary proteins such as Xrn1, Upf1, Upf2, Upf3, the LSm complex, and the Dhh1 ortholog DDX6. Proteins unique to plants and mammals include the beta propeller protein Hedls and the enhancer of decapping Edc3. Researchers know how the complex physically associates because of immunoprecipitation, while structural details of each part of the complex have been discovered by using x-ray crystallography in conjunction with protein crystallization. Each of these proteins contribute different things to the decapping complex, as discussed below.
Dcp2, as the main catalyst of the decapping process, relies on a specific pattern of amino acids called a nudix domain to align itself with the 5' cap in order to hydrolyze it. 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 carry out dephosphorylation, getting rid of a phosphate by inserting a water molecule into the bond between the phosphate and the rest of the molecule. In the case of Dcp2, it contains multiple glutamic acid side chains that are negatively charged in normal cellular conditions, and these are what allow the protein to manipulate water molecules to hydrolyze 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 remove the 5' cap, which results in the creation 7mGDP, a 7-methylguanosine with two phosphate groups attached, and a monophosphorylated mRNA strand.
Before the nudix domain is an N-terminal regulatory domain (NRD), which further helps hydrolyze the 5' mRNA cap. After the nudix domain is a C-terminal area called Box B, which helps bind Dcp2 to RNA. With all three of these main motifs, Dcp2 is able to find, bind firmly to, and hydrolyzes a 5' mRNA cap. It does this either 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 recruiting the Dcp2-Dcp1 holoenzyme. Unfortunately, Dcp2 works slowly, and needs a few other proteins to coordinate with it so it can decap mRNA in a timely manner.
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Decapping complex
The mRNA decapping complex is a protein complex in eukaryotic cells responsible for removal of the 5' cap. The active enzyme of the decapping complex is the bilobed Nudix family enzyme Dcp2, which hydrolyzes 5' cap and releases 7mGDP and a 5'-monophosphorylated mRNA. This decapped mRNA is inhibited for translation and will be degraded by exonucleases. The core decapping complex is conserved in eukaryotes. Dcp2 is activated by Decapping Protein 1 (Dcp1) and in higher eukaryotes joined by the scaffold protein VCS. Together with many other accessory proteins, the decapping complex assembles in P-bodies in the cytoplasm.
mRNA needs to be degraded, or else it 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 so the mRNA decay pathway can take care of it.
Dcp2 is the protein that actually decaps mRNA, and the rest of proteins in the complex enhance its function and allow it to hydrolyze the chemical bond attaching the mRNA to the 5' cap. The Nudix domain in Dcp2 hydrolyzes one of the bonds on the triphosphate bridge that hooks the mRNA and the 5' cap together, causing the 7-methylguanosine cap to come off and leaving the mRNA open to degradation by the exonucleases in the cell.
Both single-celled and multicellular organisms need to decap their mRNA to get rid of it, but different organisms have slightly different proteins that carry out this process. There are many proteins that stay the same, but several key differences between the single-celled (yeast) and multicellular (metazoan) decapping complexes.
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.
Higher eukaryotes have slightly different members of the decapping complex. The enzyme Dcp2 is still the catalytic subunit which forms a holoenzyme with Dcp1, and interacts with auxiliary proteins such as Xrn1, Upf1, Upf2, Upf3, the LSm complex, and the Dhh1 ortholog DDX6. Proteins unique to plants and mammals include the beta propeller protein Hedls and the enhancer of decapping Edc3. Researchers know how the complex physically associates because of immunoprecipitation, while structural details of each part of the complex have been discovered by using x-ray crystallography in conjunction with protein crystallization. Each of these proteins contribute different things to the decapping complex, as discussed below.
Dcp2, as the main catalyst of the decapping process, relies on a specific pattern of amino acids called a nudix domain to align itself with the 5' cap in order to hydrolyze it. 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 carry out dephosphorylation, getting rid of a phosphate by inserting a water molecule into the bond between the phosphate and the rest of the molecule. In the case of Dcp2, it contains multiple glutamic acid side chains that are negatively charged in normal cellular conditions, and these are what allow the protein to manipulate water molecules to hydrolyze 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 remove the 5' cap, which results in the creation 7mGDP, a 7-methylguanosine with two phosphate groups attached, and a monophosphorylated mRNA strand.
Before the nudix domain is an N-terminal regulatory domain (NRD), which further helps hydrolyze the 5' mRNA cap. After the nudix domain is a C-terminal area called Box B, which helps bind Dcp2 to RNA. With all three of these main motifs, Dcp2 is able to find, bind firmly to, and hydrolyzes a 5' mRNA cap. It does this either 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 recruiting the Dcp2-Dcp1 holoenzyme. Unfortunately, Dcp2 works slowly, and needs a few other proteins to coordinate with it so it can decap mRNA in a timely manner.
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