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Last update 23 Jan 2025

ATE1

Last update 23 Jan 2025

Basic Info

Synonyms

Arginine-tRNA--protein transferase 1, Arginyl-tRNA--protein transferase 1, arginyltransferase 1

+ [2]

Introduction

Involved in the post-translational conjugation of arginine to the N-terminal aspartate or glutamate of a protein. This arginylation is required for degradation of the protein via the ubiquitin pathway. Does not arginylate cysteine residues.

Drugs associated with ATE1

ATC-401

Target

ATE1

Mechanism

ATE1 inhibitors

Active Org.

Autotac Bio, Inc.Startup

Originator Org.

Autotac Bio, Inc.Startup

Active Indication

Muscular Dystrophy, Duchenne

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ATE1

100 Translational Medicine associated with ATE1

0 Patents (Medical) associated with ATE1

180

Literatures (Medical) associated with ATE1

17 Dec 2024·Biochemistry

Identification of an Intrinsically Disordered Region (IDR) in Arginyltransferase 1 (ATE1)

Article

Author: Oduwole, Ayomide ; Deredge, Daniel J. ; Zhang, Fangliang ; Cartwright, Misti ; Parakra, Rinky ; Smith, Aaron T.

Arginyltransferase 1 (ATE1) catalyzes arginylation, an important posttranslational modification (PTM) in eukaryotes that plays a critical role in cellular homeostasis. The disruption of ATE1 function is implicated in mammalian neurodegenerative disorders and cardiovascular maldevelopment, while posttranslational arginylation has also been linked to the activities of several important human viruses such as SARS-CoV-2 and HIV. Despite the known significance of ATE1 in mammalian cellular function, past biophysical studies of this enzyme have mainly focused on yeast ATE1, leaving the mechanism of arginylation in mammalian cells unclear. In this study, we sought to structurally and biophysically characterize mouse (Mus musculus) ATE1. Using size-exclusion chromatography (SEC), small-angle X-ray scattering (SAXS), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), assisted by AlphaFold modeling, we found that mouse ATE1 is structurally more complex than yeast ATE1. Importantly, our data indicate the existence of an intrinsically disordered region (IDR) in all mouse ATE1 splice variants. However, comparative HDX-MS analyses show that yeast ATE1 does not have such an IDR, consistent with prior X-ray, cryo-EM, and SAXS analyses. Furthermore, bioinformatics approaches reveal that mammalian ATE1 sequences, as well those as in a large majority of other eukaryotes, contain an IDR-like sequence positioned in proximity to the ATE1 GNAT active-site fold. Computational analysis suggests that the IDR facilitates the formation of a complex between ATE1 and tRNA^Arg, adding a new complexity to the ATE1 structure and providing new insights for future studies of ATE1 functions.

21 Sep 2024·Journal of Biomolecular Structure and Dynamics

Structural analysis of human ATE1 isoforms and their interactions with Arg-tRNA _Arg

Article

Author: Naga, Rahul ; Kar, Parimal ; Mattaparthi, Venkata Satish Kumar ; Bhattacharjee, Arghyadeep ; Bose, Avishek ; Mukherjee, Oindrilla ; Saha, Sougata ; Poddar, Sayan

Posttranslational protein arginylation has been shown as a key regulator of cellular processes in eukaryotes by affecting protein stability, function, and interaction with macromolecules. Thus, the enzyme Arginyltransferase and its targets, are of immense interest to modulate cellular processes in the normal and diseased state. While the study on the effect of this posttranslational modification in mammalian systems gained momentum in the recent times, the detail structures of human ATE1 (hATE1) enzymes has not been investigated so far. Thus, the purpose of this study was to predict the overall structure and the structure function relationship of hATE1 enzyme and its four isoforms. The structure of four ATE1 isoforms were modelled and were docked with 3'end of the Arg-tRNA_Arg which acts as arginine donor in the arginylation reaction, followed by MD simulation. All the isoforms showed two distinct domains. A compact domain and a somewhat flexible domain as observed in the RMSF plot. A distinct similarity in the overall structure and interacting residues were observed between hATE1-1 and X4 compared to hATE1-2 and 5. While the putative active sites of all the hATE1 isoforms were located at the same pocket, differences were observed in the active site residues across hATE1 isoforms suggesting different substrate specificity. Mining of nsSNPs showed several nsSNPs including cancer associated SNPs with deleterious consequences on hATE1 structure and function. Thus, the current study for the first time shows the structural differences in the mammalian ATE1 isoforms and their possible implications in the function of these proteins.Communicated by Ramaswamy H. Sarma.

01 Sep 2024·Methods

Copper catalyzed cycloaddition for the synthesis of non isomerisable 2′ and 3′-regioisomers of arg-tRNAarg

Article

Author: Etheve-Quelquejeu, Mélanie ; Sargueil, Bruno ; Ponchon, Luc ; Iannazzo, Laura ; Guerineau, Vincent ; Zhang, Yi ; Abeywansha, Thilini ; Afandizada, Yusif

In this report, non-isomerisable analogs of arginine tRNA (Arg-triazole-tRNA) have been synthesized as tools to study tRNA-dependent aminoacyl-transferases. The synthesis involves the incorporation of 1,4 substituted-1,2,3 triazole ring to mimic the ester bond that connects the amino acid to the terminal adenosine in the natural substrate. The synthetic procedure includes (i) a coupling between 2'- or 3'-azido-adenosine derivatives and a cytidine phosphoramidite to access dinucleotide molecules, (ii) Cu-catalyzed cycloaddition reactions between 2'- or 3'-azido dinucleotide in the presence of an alkyne molecule mimicking the arginine, providing the corresponding Arg-triazole-dinucleotides, (iii) enzymatic phosphorylation of the 5'-end extremity of the Arg-triazole-dinucleotides with a polynucleotide kinase, and (iv) enzymatic ligation of the 5'-phosphorylated dinucleotides with a 23-nt RNA micro helix that mimics the acceptor arm of arg-tRNA or with a full tRNA^arg. Characterization of nucleoside and nucleotide compounds involved MS spectrometry, ¹H, ¹³C and ³¹P NMR analysis. This strategy allows to obtain the pair of the two stable regioisomers of arg-tRNA analogs (2' and 3') which are instrumental to explore the regiospecificity of arginyl transferases enzyme. In our study, a first binding assay of the arg-tRNA micro helix with the Arginyl-tRNA-protein transferase 1 (ATE1) was performed by gel shift assays.

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