Folding ribosomal RNA requires paired tagging sequence
Structure of the RNA-tagging machinery shows that only one pair of proteins (blue) can add tags to the RNA (red) at a time.
To fold RNA that makes ribosomes, pairs of methyl tags must be added in specific order
Detailed 3D structure of folding machinery attached to RNA
Obtained by combination of nuclear magnetic resonance (NMR) and small angle neutron scattering (SANS)
An important step in building ribosomes – the cell’s protein factories – is like a strictly choreographed dance, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered. To build these factories, other ‘machines’ inside the cell have to produce specific RNA molecules and fold them into the right shape, then combine the folded RNA with proteins to form a working ribosome. Like a budding origami artist pencilling in the folds, the cell uses tags called methyl groups to help mark where and how an RNA molecule should be folded. In work published online today in Nature, the scientists have discovered that pairs of these tags are added in a specific order. The study combined nuclear magnetic resonance at EMBL and neutron scattering at the Institut Laue-Langevin (ILL) in Grenoble, France.
Led by Teresa Carlomagno at EMBL, the scientists were able to determine the 3D structure of the complex that adds methyl tags to the RNA, with the RNA molecules attached. They discovered that the different components of this tagging machine pair up and move in sequence, like dancers following a set choreography.
“We found that the complex has four copies of each protein, and four methylation sites on the RNA, but those methylation sites aren’t all the same,” Carlomagno says. “They come in pairs, and one pair has to be methylated before the other.”
The fact that the pairs of tags have to be added in a particular order could be a way for the cell to control how the RNA is folded, and ultimately when and where ribosomes are formed, the scientists believe.
The study provides a detailed view of the complex in a form that’s very close to what’s found inside our cells. To obtain it, the EMBL scientists teamed up with Frank Gabel at the Institut Laue-Langevin (ILL) and the Institut de Biologie Structurale (IBS), both in Grenoble, France, to combine their expertise in nuclear magnetic resonance (NMR) with the Gabel lab's skills in small angle neutron scattering (SANS).
Lapinaite, A., Simon, B., Skjaerven, L., Rakwalska-Bange, M., Gabel, F. & Carlomagno, T. The structure of the Box C/D enzyme reveals regulation of rRNA methylation. Published online in Nature on 14 October 2013. DOI: 10.1038/nature12581.
Post-transcriptional modifications are essential to the cell life cycle, as they impact both pre-rRNA processing and ribosome assembly. The Box C/D RNP enzyme that methylates rRNA at the 2’-O-ribose uses a multitude of guide RNAs as templates for the recognition of rRNA target sites. Two methylation guide sequences are combined on each guide RNA, the significance of which has remained unclear. Here, we use a powerful combination of NMR spectroscopy and small angle neutron scattering to solve the structure of the 390 kDa archaeal RNP enzyme bound to substrate RNA. We show that the two methylation guide sequences are located in different environments in the complex and that the methylation of physiological substrates targeted by the same guide RNA occurs sequentially. This structure provides a means for differential control of methylation levels at the two sites and at the same time offers an unexpected regulatory mechanism for rRNA folding.
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