The structure shows that the lysine acetyl transferase (KAT) domain and the S-adenosylmethionine binding domain (SAM) share a large and highly conserved interface that creates a specific tRNA binding pocket and forms a composite active site. We recently determined the crystal structure of full-length Elp3 from a bacterial homolog (DmcElp3), which shows high sequence similarity to Elp3s from different organisms, including yeast and humans 32. Crystal structures are currently available for the homo-dimer of the Elp1 C-terminus 29, Elp2 30, and the RecA-like Elp456 hetero-hexamer 20 31. Shortly after the initial description of the three-component Elongator sub-complex (Elp123) 27, an additionally associated sub-complex containing subunits Elp4, Elp5, and Elp6 28 was identified under milder purification conditions. All subunits are highly conserved among eukaryotes 21, which has also been experimentally proven by cross species complementation analyses of genes encoding individual subunits and subdomains for yeast, insects, worms, plants, and humans 15 22 23 24 25 26. The fully assembled Elongator complex contains two copies of each of its six subunits in vivo 20 and has an estimated molecular weight of ~850 kDa. The cellular role of Elongator is of fundamental clinical relevance, as mutations affecting the integrity and activity of this macromolecular complex are related to the onset of neurodegenerative diseases 14 15 16, cancer 17 18, and intellectual disabilities 19.
ULTIMATE TAP TITANS 2 OPTIMIZER 2.2 FULL
In particular, it is currently unclear how tRNA is delivered to the active center and how the high modification turnover can be achieved in the context of the full complex. Nevertheless, the detailed chemistry of the Elongator modification reaction is insufficiently described, and the role of the resulting modifications is not fully understood 11 12 13.
The eukaryotic Elongator complex has been associated with a plethora of cellular activities 8 9 10, but nowadays, it is widely accepted that the main cellular function of the Elongator complex is the formation of 5-methoxycarbonylmethyl-uridine (mcm 5U), 5-methoxycarbonylmethyl-2-thio-uridine (mcm 5s 2U), and 5-carbamoylmethyl-uridine (ncm 5U) in the wobble base position of 11 eukaryotic tRNAs 10. Interestingly, expansion of tRNA gene copy numbers and isoacceptors correlate well with an increase in different tRNA modification enzymes, suggesting an evolutionary selection for optimizing translational efficiency and accuracy via different modification mechanisms 7. Mainly because they influence the recognition rate and affinity between incoming tRNAs and codons in the A site of the translating ribosome 4 5 6.
Previous studies indicated that specific base modifications in the wobble base position of tRNAs are crucial to maintain these highly dynamic and complex mechanisms. Tel: +49 62 E-mail: ĭuring the elongation phase of the ribosome-mediated translation process, transient pausing events support proper domain folding of the nascent polypeptide chains, which gain their three-dimensional conformations immediately after they have left the exit tunnel of the ribosomes, a process sometimes facilitated by chaperones 1 2 3. 9 Present address: CRBM – CNRS UMR5237, Montpellier, France.8 Present address: Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.7 Present address: School of Biological Sciences, University of Auckland, Auckland, New Zealand.6 Max Planck Research Group at the Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.5 Institute of Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.3 CNRS, IGBMC UMR 7104, Illkirch, France.2 Université de Strasbourg, IGBMC, Illkirch, France.1 European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
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