tRNAModification by Elongator Protein 3 (Elp3)

Abstract

Elongator 3 (Elp3) represents the enzymatically active subunit of the multisubunit Elongator complex that catalyzes the first step of the 5‐methoxycarbonylmethyl and 5‐carbamoylmethyl modification reaction at uridine bases in the wobble position of tRNAs. These modifications are essential for accurate protein translation rates and proteome homeostasis, and their loss is detrimental, leading to cellular dysfunctions, neurodegenerative diseases, and cancers. The electron microscopy structure of the Elongator and the crystal structure of Elp3 have recently been resolved, but details of the enzymatic reaction still remain elusive. One copy of Elp3 is located in each center of the two Elp123 lobes, and unlike other known modifying enzymes, Elp3 consists of two functional domains, namely radical S ‐adenosyl methionine and lysine acetyltransferase domains. The SAM domain harbors an iron–sulfur (Fe–S) cluster, which is essential for the integrity and activity of the complex. In addition, Elp3 coordinates zinc and interacts with Kti11, a regulatory factor that coordinates iron and zinc, most likely acting as an electron donor for the respective Fe–S cluster of Elp3. Through the unique combination and interplay of its two domains, Elp3 is able to cleave SAM, generate necessary deoxy radicals, and transfer an acetyl radical from acetyl‐CoA to C5 of U 34 .

Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

“…In support of this notion, archaeal Elp3 from Methanocaldococcus infernus has been shown to modify U 34 in the anticodon loop of synthetic tRNA Arg UCU substrates iin vitro in a radical SAM dependent reaction containing electron donor (Na 2 S 2 O 4 ), SAM and acetyl-CoA [93]. Moreover, sophisticated insights into the basis and mechanism for Elongator’s tRNA modification capacity have been recently provided through elegant structure-functional work on prokaryotic Elp3 from Dehalococcoides mccartyi and holo-Elongator from the yeast Saccharomyces cerevisiae [86,87,88,95,96,97].…”

How Elongator Acetylates tRNA Bases

“…Apart from bacterial, archaeal, and yeast Elp3s, the enzymatic activities of Elongator have been investigated in many other eukaryotic organisms, including worms, flies, zebrafish, plants, mice, and humans [30]. However, quantitative biochemical and biophysical in vitro analyses of Elongator's modification activities have been limited by severe technical challenges.…”