Abstract
Elp3, the catalytic subunit of the eukaryotic Elongator complex, is a lysine acetyltransferase that acetylates the C5 position of wobble-base uridines (U34) in transfer RNAs (tRNAs). This Elongator-dependent RNA acetylation of anticodon bases affects the ribosomal translation elongation rates and directly links acetyl-CoA metabolism to both protein synthesis rates and the proteome integrity. Of note, several human diseases, including various cancers and neurodegenerative disorders, correlate with the dysregulation of Elongator’s tRNA modification activity. In this review, we focus on recent findings regarding the structure of Elp3 and the role of acetyl-CoA during its unique modification reaction.
Highlights
Acetyl coenzyme A is an essential cofactor that serves as an acetyl group donor and is crucial for cellular metabolism and specific regulatory cascades
Two distinct sites of acetylation are known in proteins—namely, (i) the α-amino group at the N-terminus and (ii) the ε-amino group at the side chain of lysine residues. The former is catalyzed by N-terminal acetyltransferases (NATs) and the latter is executed by lysine acetyltransferases (KATs)
This study provides an initial model of how Elongatorregulation is directly related to ER stress or unfolded protein response (UPR), that are often associated with neurological disorders
Summary
Acetyl coenzyme A (acetyl-CoA) is an essential cofactor that serves as an acetyl group donor and is crucial for cellular metabolism and specific regulatory cascades. In a subset of mammalian tRNAs, the mcm5U34-modified wobble base is further processed to 5-methoxy-carbonyl-methyl-2-thio-uridine (mcm5s2U34) or 5-methoxy-carbonyl-hydroxymethyl-uridine (mchm5U34) These chemical modifications provide additional spatial restraints for the codon-anticodon base pairing during ribosomal decoding and translation elongation. In contrast to the formation of a carbamoyl group by common protein acetyltransferases, Elp connects the methyl group of the acetyl residue with the C5 atom of the targeted uracil base. This type of reaction is unique to Elp proteins and, in addition to a KAT domain, it requires an additional radical S-adenosyl methionine (rSAM) domain to execute its full modification activity. The implications of Elongator dysfunction in various organisms and the pathological consequences of other tRNA modification enzymes are well-summarized by recently published reviews [16,17,18]
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