The Elongator subunit Elp3 is a non-canonical tRNA acetyltransferase

Ting-Yu Lin,Nour El Hana Abbassi,Andrzej Chramiec-Głąbik,Sebastian Glatt,Małgorzata Jemioła-Rzemińska,Karol Zakrzewski,Jan Różycki

doi:10.1038/s41467-019-08579-2

Ting-Yu Lin, Nour El Hana Abbassi + Show 5 more

Open Access

https://doi.org/10.1038/s41467-019-08579-2

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Abstract

The Elongator complex catalyzes posttranscriptional tRNA modifications by attaching carboxy-methyl (cm5) moieties to uridine bases located in the wobble position. The catalytic subunit Elp3 is highly conserved and harbors two individual subdomains, a radical S-adenosyl methionine (rSAM) and a lysine acetyltransferase (KAT) domain. The details of its modification reaction cycle and particularly the substrate specificity of its KAT domain remain elusive. Here, we present the co-crystal structure of bacterial Elp3 (DmcElp3) bound to an acetyl-CoA analog and compare it to the structure of a monomeric archaeal Elp3 from Methanocaldococcus infernus (MinElp3). Furthermore, we identify crucial active site residues, confirm the importance of the extended N-terminus for substrate recognition and uncover the specific induction of acetyl-CoA hydrolysis by different tRNA species. In summary, our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme.

Highlights

The Elongator complex catalyzes posttranscriptional tRNA modifications by attaching carboxy-methyl moieties to uridine bases located in the wobble position
We found that several potent key residues residing in the acetyl-CoA binding pocket (e.g. K77, K193, E386, and Y441) are conserved among various Elp3s and showed that the equivalent single amino acid substitutions in yeast lead to Elongator loss-of-function phenotypes
All known Elp3s share high sequence similarity, eukaryotic Elp3s are embedded in the large Elongator complex and the modification reaction requires five other Elongator subunits and several regulatory factors[56,57]

Summary

Introduction

The Elongator complex catalyzes posttranscriptional tRNA modifications by attaching carboxy-methyl (cm5) moieties to uridine bases located in the wobble position. The functions of tRNA modifications can be separated into three main categories depending on the modified positions, either (i) stabilizing the structural integrity of the core tRNA fold[4], (ii) contributing to the correct amino-acylation of respective tRNAs at the acceptor stem loop[5] or (iii) enhancing the decoding potential and translation fidelity at the ribosome[6,7]. The latter group of tRNA modifications is mostly found around the anticodon stem loop (ASL), at the so-called “hot spot” positions 34 and 372,7,8. Patientderived mutations and deficiencies in different Elongator subunits are associated with severe human diseases[37,38], such as cancer[39] and neurodegenerative diseases[40], including familial dysautonomia[41], amyotrophic lateral sclerosis[42], intellectual disabilities[43], and ataxia[44]

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