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Information on EC 2.3.2.8 - arginyltransferase and Organism(s) Mus musculus and UniProt Accession Q9Z2A5
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2.3.2.8 arginyltransferaseIUBMB Comments
Requires 2-sulfanylethan-1-ol (2-mercaptoethanol) and a univalent cation. Peptides and proteins containing an N-terminal glutamate, aspartate or cystine residue can act as acceptors.
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Word Map
- 2.3.2.8
-
arginylation
-
2.5.1.18
-
rx:glutathione
- rx
-
n-degrons
-
polyubiquitylates
- medicine
- agriculture
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
arginyltransferase, r-transferase, arginyl-trna-protein transferase, arginyl-trna protein transferase, arginyltransferase 1, arginyl transferase, arg-transferase, arginyl-trna:protein arginyltransferase, arginyl-transferase, ate1-1, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
arginyl tRNA transferase
-
-
-
-
arginyl-transfer ribonucleate-protein aminoacyltransferase
-
-
-
-
arginyl-transfer ribonucleate-protein transferase
-
-
-
-
arginyl-tRNA protein transferase
Ate1-3
Ate1-4
L-arginyltransferase
-
-
-
-
R-transferase
arginyl-tRNA protein transferase
-
-
-
-
R-transferase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acyl group transfer
arginylation
Acyl group transfer
Acyl group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
L-arginyl-tRNAArg:protein arginyltransferase
Requires 2-sulfanylethan-1-ol (2-mercaptoethanol) and a univalent cation. Peptides and proteins containing an N-terminal glutamate, aspartate or cystine residue can act as acceptors.
CAS REGISTRY NUMBER
COMMENTARY
37257-24-2
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-arginyl-tRNAArg + alpha cardiac actin
tRNAArg + L-arginyl-[alpha cardiac actin]
-
-
-
?
L-arginyl-tRNAArg + alpha-synuclein
tRNAArg + L-arginyl-[alpha-synuclein]
alpha-syn is arginylated in vitro and in vivo
-
-
?
L-arginyl-tRNAArg + Rgs16 regulator of G protein
tRNAArg + L-arginyl-[Rgs16 regulator of G protein]
-
-
-
?
L-arginyl-tRNAArg + RGS4 protein
tRNAArg + L-arginyl-[RGS4 protein]
-
-
-
?
L-arginyl-tRNAArg + Rgs4 regulator of G protein
tRNAArg + L-arginyl-[Rgs4 regulator of G protein]
-
-
-
?
L-arginyl-tRNAArg + Rgs5 regulator of G protein
tRNAArg + L-arginyl-[Rgs5 regulator of G protein]
-
-
-
?
L-Arg-tRNAArg + Cys-beta-galactosidase
tRNaArg + L-Arg-L-Cys-beta-galactosidase
-
substrate only for isoforms Ate1-3, Ate1-4
-
-
?
L-Arg-tRNAArg + glucose-related protein 78
tRNAArg + L-Arg-[glucose-related protein 78]
-
-
-
-
?
L-Arg-tRNAArg + protein-disulfide isomerase
tRNAArg + L-Arg-[protein-disulfide isomerase]
-
-
-
-
?
L-arginyl-tRNA + L-Asp-beta-galactosidase
tRNA + L-arginyl-L-Asp-beta-galactosidase
-
-
-
-
?
L-arginyl-tRNAArg + alpha lactalbumin
tRNAArg + L-arginyl-[lactalbumin]
-
-
-
-
?
L-arginyl-tRNAArg + Asp-beta-galactosidase
tRNAArg + L-arginyl-Asp-beta-galactosidase
-
-
-
-
?
L-arginyl-tRNAArg + BiP/GRP78 protein
tRNAArg + L-arginyl-[BiP/GRP78 protein]
-
-
-
-
?
L-arginyl-tRNAArg + bovine alpha-lactalbumin
tRNAArg + L-arginyl-[bovine alpha-lactalbumin]
-
higher activity is detected with isoforms ATE1-1 (100%) and ATE1-2 (85%), and weaker activity is detected with isoforms ATE1-3 (18%) and ATE1-4 (4%)
-
-
?
L-arginyl-tRNAArg + calreticulin
tRNAArg + L-arginyl-[calreticulin]
-
-
-
-
?
L-arginyl-tRNAArg + L-Arg-[beta-galactosidase]
tRNAArg + L-Arg-L-Arg-[beta-galactosidase]
-
-
-
-
?
L-arginyl-tRNAArg + L-Glu-[beta-galactosidase]
tRNAArg + L-Arg-L-Glu-[beta-galactosidase]
-
-
-
-
?
L-arginyl-tRNAArg + L-Met-[beta-galactosidase]
tRNAArg + L-Arg-L-Met-[beta-galactosidase]
-
-
-
-
?
L-arginyl-tRNAArg + protein disulfide isomerase
tRNAArg + L-arginyl-[protein disulfide isomerase]
-
-
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
ATE1-2p is less active than ATE1-1p
-
-
?
L-arginyl-tRNAArg + protein
tRNAArg + L-arginyl-[protein]
-
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
-
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
addition to amino-terminus
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
involved in ubiquitin mediated protein degradation
-
-
?
L-arginyl-tRNAArg + bovine serum albumin
tRNAArg + L-arginyl-[bovine serum albumin]
-
-
-
-
?
L-arginyl-tRNAArg + bovine serum albumin
tRNAArg + L-arginyl-[bovine serum albumin]
-
high activity is detected with isoforms ATE1-1 (100%) and ATE1-2 (95%), and weaker activity is detected with isoforms ATE1-3 (10%) and ATE1-4 (4%)
-
-
?
L-arginyl-tRNAArg + protein
tRNAArg + L-arginyl-[protein]
-
-
-
-
?
L-arginyl-tRNAArg + protein
tRNAArg + L-arginyl-[protein]
-
the enzyme catalyzes mid-chain arginylation of proteins at side chain carboxylates in vivo. N-terminal arginylation of the peptide substrates occurs by the alpha amino group
-
-
?
additional information
?
-
the Arg/N-end rule-mediated autophagic flux regulator might be a direct substrate of ATE1, rather than UBR1 or UBR2
-
-
-
additional information
?
-
the four mouse ATE1 isoforms have different, partially overlapping substrate specificity toward their N-terminal target sites, detailed overview. The four mouse ATE1 isoforms show prominent and consistent differences in target site specificity, both at the N-terminus and the side chain sites. At the N-terminal sites, only three of the four ATE1 isoforms (ATE1-1, 2, and 3) show high preference for the peptides containing N-terminal D and E. ATE1-4 do not appear to target peptides containing N-terminal E. At the same time all four isoforms, to a various degree, show prominent reactivity with the peptides bearing N-terminal C. Even more strikingly, ATE1-1, unlike any other ATE1 isoforms, appears to be reactive with additional N-terminal sites not seen with other ATE1 isoforms, including Q and, weakly, H. Thus, it appears that N-terminal target site specificity of ATE1-1 may be broader than other ATE1 isoforms and potentially include non-canonical N-terminal residues. The four ATE1 isoforms also show different reactivity with the peptides bearing side chain target sites. In the case of ATE1-1 and ATE1-2, the signal with these peptides containing side chain target sites is substantially lower or absent compared to the peptides containing favorable N-terminal target sites. Side chain arginylation of one of these peptides with ATE1-2 in solution. It appears likely that the peptide array format is unfavorable for side chain targeting by these ATE1 isoforms. Isozyme ATE1-1 catalyzes arginylation of non-canonical residues. Identification of the arginylation-favorable sequence motif
-
-
-
additional information
?
-
-
the four mouse ATE1 isoforms have different, partially overlapping substrate specificity toward their N-terminal target sites, detailed overview. The four mouse ATE1 isoforms show prominent and consistent differences in target site specificity, both at the N-terminus and the side chain sites. At the N-terminal sites, only three of the four ATE1 isoforms (ATE1-1, 2, and 3) show high preference for the peptides containing N-terminal D and E. ATE1-4 do not appear to target peptides containing N-terminal E. At the same time all four isoforms, to a various degree, show prominent reactivity with the peptides bearing N-terminal C. Even more strikingly, ATE1-1, unlike any other ATE1 isoforms, appears to be reactive with additional N-terminal sites not seen with other ATE1 isoforms, including Q and, weakly, H. Thus, it appears that N-terminal target site specificity of ATE1-1 may be broader than other ATE1 isoforms and potentially include non-canonical N-terminal residues. The four ATE1 isoforms also show different reactivity with the peptides bearing side chain target sites. In the case of ATE1-1 and ATE1-2, the signal with these peptides containing side chain target sites is substantially lower or absent compared to the peptides containing favorable N-terminal target sites. Side chain arginylation of one of these peptides with ATE1-2 in solution. It appears likely that the peptide array format is unfavorable for side chain targeting by these ATE1 isoforms. Isozyme ATE1-1 catalyzes arginylation of non-canonical residues. Identification of the arginylation-favorable sequence motif
-
-
-
additional information
?
-
usage of DD-bta15-GFP assay for an 'in-lysate' reaction to examine arginylation activity in cell extracts
-
-
-
additional information
?
-
-
usage of DD-bta15-GFP assay for an 'in-lysate' reaction to examine arginylation activity in cell extracts
-
-
-
additional information
?
-
-
isoforms Ate1-3, Ate1-4, no substrate: proteins containing N-terminal Asp or Glu
-
-
?
additional information
?
-
-
ATE1 is capable of self-arginylation in vitro and in vivo
-
-
?
additional information
?
-
-
the arginylation reaction does not require the formation of an ATE1-arginyl-tRNA synthetase complex or the presence of ATP
-
-
?
additional information
?
-
-
Liat1 protein binds to the mouse Ate1 enzyme, but is apparently not arginylated by it
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
-
-
?
L-arginyl-tRNAArg + alpha-synuclein
tRNAArg + L-arginyl-[alpha-synuclein]
alpha-syn is arginylated in vitro and in vivo
-
-
?
L-arginyl-tRNAArg + RGS4 protein
tRNAArg + L-arginyl-[RGS4 protein]
-
-
-
?
L-Arg-tRNAArg + glucose-related protein 78
tRNAArg + L-Arg-[glucose-related protein 78]
-
-
-
-
?
L-Arg-tRNAArg + protein-disulfide isomerase
tRNAArg + L-Arg-[protein-disulfide isomerase]
-
-
-
-
?
L-arginyl-tRNAArg + BiP/GRP78 protein
tRNAArg + L-arginyl-[BiP/GRP78 protein]
-
-
-
-
?
L-arginyl-tRNAArg + calreticulin
tRNAArg + L-arginyl-[calreticulin]
-
-
-
-
?
L-arginyl-tRNAArg + protein disulfide isomerase
tRNAArg + L-arginyl-[protein disulfide isomerase]
-
-
-
-
?
additional information
?
-
the Arg/N-end rule-mediated autophagic flux regulator might be a direct substrate of ATE1, rather than UBR1 or UBR2
-
-
-
L-arginyl-tRNAArg + protein
tRNAArg + L-arginyl-[protein]
-
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
-
-
-
?
L-arginyl-tRNAArg + acceptor protein
tRNAArg + L-arginyl-[acceptor protein]
-
involved in ubiquitin mediated protein degradation
-
-
?
L-arginyl-tRNAArg + protein
tRNAArg + L-arginyl-[protein]
-
-
-
-
?
L-arginyl-tRNAArg + protein
tRNAArg + L-arginyl-[protein]
-
the enzyme catalyzes mid-chain arginylation of proteins at side chain carboxylates in vivo. N-terminal arginylation of the peptide substrates occurs by the alpha amino group
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
hemin
-
Fe3+-heme, inhibits arginyl-transferase through a redox mechanism that involves the formation of disulfide between the enzymes Cys-71 and Cys-72 residues
additional information
para-chloroamphetamine, PCA, a specific inhibitor of the arginylation branch of the pathway (Arg/N-end rule pathway). PCA significantly alters various biological pathways, including cellular responses to stress, nutrient, and DNA damage, which are also closely involved in modulation of autophagic responses. Treatment with para-chloroamphetamine (PCA) delays the fusion of autophagosomes with lysosomes and leads to the accumulation of autophagic markers. Analysis of PCA effects in wild-type and mutant (ubr1-/- ubr2-/-) MEFs. The direct targets of PCA are UBR1 and UBR2 proteins, not ATE1, an upstream component of the Arg/N-end rule pathway
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00034
merbromin
Mus musculus
-
in 50 mM HEPES pH 7.5, 25 mM KCl, 15 mM MgCl2, 0.1 mM dithiothreitol, at 37°C
0.00097
Reactive blue 2
Mus musculus
-
in 50 mM HEPES pH 7.5, 25 mM KCl, 15 mM MgCl2, 0.1 mM dithiothreitol, at 37°C
0.00043
suramin
Mus musculus
-
in 50 mM HEPES pH 7.5, 25 mM KCl, 15 mM MgCl2, 0.1 mM dithiothreitol, at 37°C
0.00028
Tannic acid
Mus musculus
-
in 50 mM HEPES pH 7.5, 25 mM KCl, 15 mM MgCl2, 0.1 mM dithiothreitol, at 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
expression of ATE1 is prominent in the developing brain and spinal cord, and this pattern overlaps with the migration path of neural stem cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Ate1 mRNA localized to the tips of the growth cones, likely due to zipcode-mediated targeting. Both ATE1 and arginylated beta-actin are localized at the growth cones
additional information
additional information
ATE1 prominently localizes to the growth cones, in addition to the cell bodies. The Ate1 mRNA sequence reveals the existence of putative zipcode-binding sequences involved in mRNA targeting to the cell periphery and local translation at the growth cones
-
additional information
-
ATE1 prominently localizes to the growth cones, in addition to the cell bodies. The Ate1 mRNA sequence reveals the existence of putative zipcode-binding sequences involved in mRNA targeting to the cell periphery and local translation at the growth cones
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
malfunction
physiological function
additional information
evolution
ATE1 Arg-transferase is an evolutionarily conserved protein present in all eukaryotes from fungi to animals
evolution
eukaryotic systems including Saccharomyces cerevisiae (budding yeast), mouse cells, and human cells, all contain the evolutionarily conserved ATE1 gene
malfunction
ATE1-null mice show severe intracerebral hemorrhages and cystic space near the neural tubes. The ATE1-/- brain shows defective G-protein signaling. Reduced mitosis in ATE1-/- neuroepithelium and a significantly higher nitric oxide concentration in ATE1-/- brain are observed. In ATE1-null murine embryos, neural-tube genesis is severely defective, and this problem may be the primary cause of embryonic mortality of the mutant mice. ATE1 expression is more prominent in the embryonic brain and spinal cord than in the heart. ATE1-null embryonic brain shows stabilized regulators of G protein signaling (RGS) proteins, defective G protein signaling, and a higher concentration of NO. Proliferation of ATE1-/- neuroepithelial cells in the developing primary neural tube is significantly impaired. Stabilized RGS proteins in ATE1-null mice and reduced activities of downstream effectors, overview
malfunction
blocking the Arg/N-end rule pathway significantly impaired the fusion of autophagosomes with lysosomes. The inhibition of the Arg/N-end rule pathway with para-chloroamphetamine (PCA) significantly elevates levels of MAPT and huntingtin aggregates, accompanied by increased numbers of LC3 and SQSTM1 puncta. Cells treated with the Arg/N-end rule inhibitor become more sensitized to proteotoxic stress-induced cytotoxicity. Treatment with PCA delays the fusion of autophagosomes with lysosomes and leads to the accumulation of autophagic markers
malfunction
conditional knockout mice with Ate1 deletion in the nervous system driven by Nestin promoter (Nes-Ate1 mice) are weaker than wild-type mice, resulting in low postnatal survival rates, and have abnormalities in the brain that suggest defects in neuronal migration. Cultured Ate1 knockout neurons show a reduction in the neurite outgrowth and the levels of doublecortin and F-actin in the growth cones. A lack of beta-actin arginylation leads to a marked reduction in growth cone spreading, accompanied by the corresponding decrease in the actin polymer. Nes-Ate1 mice develope to full term and are born at the expected about 25% ratio, with the body weight and appearance at birth indistinguishable from their wild-type littermates. However, these newborn mice are visibly less active than wild-type, easily pushed away by their littermates during feeding and show no inclination to explore the environment within days after birth. These newborns exhibit dramatically reduced growth in the first days of postnatal life, likely due to their inability to compete for the mother's milk with wild-type littermates. Complete Ate1 knockout mice die at E12.5-E14.5 during development
malfunction
deletion of Ate1 in mice leads to embryonic lethality and impairments in multiple physiological systems, including cardiovascular development, angiogenesis, muscle contraction, and cell migration. Lack of arginylation leads to increased Alpha synuclein (alpha-syn) aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways. In the mouse brain, lack of arginylation leads to an increase in alpha-syn's insoluble fraction, accompanied by behavioral changes characteristic for neurodegenerative pathology. Lack of arginylation in the brain leads to neurodegeneration
malfunction
knockout of ATE1 gene in MEFs significantly reduces apoptotic rates in the presence of microbial alkaloid toxin staurosporine (STS) compared to wild-type. Similar results are observed with a different stressor, CdCl2
metabolism
the arginylation branch of the N-end rule pathway is a ubiquitin-mediated proteolytic system in which post-translational conjugation of Arg by ATE1-encoded Arg-tRNA-protein transferase to N-terminal Asp, Glu, or oxidized Cys residues generates essential degradation signals
metabolism
the arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins. In the Arg/N-end rule pathway, a main process, that generates a primary destabilizing residue, is the posttranslational conjugation of Arg to pro-N-degrons such as Asp, Glu, and oxidized Cys. This conjugation is solely mediated by ATE1-encoded Arg-tRNA-protein transferase. Arg/N-end rule pathway-dependent degradation of Arg-HSPA5 is a critical regulatory step for autophagosome maturation. Molecular mechanism of Arg/N-end rule dependent autophagic inhibition, oerview
physiological function
Ate1 plays a role in the regulation of cytoskeleton and is essential for cardiovascular development and angiogenesis
physiological function
N-terminal arginylation of intracellular proteins by Arg-tRNA-protein transferase is a part of the N-end rule pathway of protein degradation
physiological function
posttranslational arginylation mediated by Ate1 is essential for cardiovascular development and angiogenesis and directly affects the myocardium structure in the developing heart
physiological function
arginyltransferase 1 (Ate1) mediates protein arginylation, a protein posttranslational modification (PTM) in eukaryotic cells. Ate1 is required to suppress mutation frequency in yeast and mammalian cells during DNA-damaging conditions such as ultraviolet irradiation. Ate1 and arginylation are upregulated during stress and are responsible for cell death, role of Ate1/arginylation in stress response, overview. Ate1 is essential for the suppression of mutagenesis during DNA-damaging stress. Growth arrest and cell death during stress could be interpreted as a mechanism to prevent incorporation of damaged genetic material or transmission of mutation to the subsequent generations
physiological function
ATE1 Arg-transferase is the key enzyme in the Arg/N-end rule pathway. ATE1 is required for degradation of regulators of G protein signaling (RGS) proteins and GPCR signaling, regulation, overview. Essential role of N-terminal arginylation in neural tube development. The crucial role of ATE1 in neural tube development is directly related to proper turn-over of the RGS4 protein, which participate in the oxygen-sensing mechanism in the cells. Degradation of the RGS4 protein by ATE1 is closely associated with the migration or differentiation of neural crest cells during embryogenesis. Neural crest cells migrate into the heart and vessels
physiological function
protein arginylation is a posttranlsational modification mediated by arginyltransferase ATE1 that transfers Arg from tRNA directly to protein targets. Protein arginylation targets alpha-synuclein, facilitates normal brain health, and prevents neurodegeneration. Alpha-synuclein (alpha-syn) is a central player in neurodegeneration. It is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a mid-chain mechanism that targets the acidic side chains of E46 and E83. alpha-Syn arginylation can be a factor that facilitates normal alpha-syn folding and function in vivo. Arginylation reduces aggregation of pre-formed alpha-syn fibrils and partially prevents alpha-syn-induced seeding of pathological aggregates in cultured neurons, overview
physiological function
protein arginylation mediated by arginyltransferase ATE1 is an emerging regulatory modification that consists of posttranslational tRNA-mediated addition of arginine to proteins. Arginyltransferase ATE1 regulates embryogenesis and actin cytoskeleton. Role of ATE1 in brain development and neuronal growth. Zipcode-mediated co-targeting of Ate1 and beta-actin mRNA leads to localized co-translational arginylation of beta-actin that drives the growth cone migration and neurite outgrowth. The mechanism that regulates neurite outgrowth during development via arginylation and potentially involves targeted cotranslational arginylation of beta-actin in the developing growth cones, overview. ATE1 is targeted to the tips of the growing neurites where it arginylates beta-actin
physiological function
protein arginylation, mediated by the arginyltransferase ATE1, is a posttranslational modification that is essential for mammalian embryogenesis, regulates many fundamental biological processes, and targets a large number of proteins in vivo. In mammals, ATE1 is represented by four homologous isoforms ATE1-1, 2, 3, and 4, generated by alternative splicing from a single gene and reported in different studies to have varying activity, substrate specificity, and tissue-specific expression. In addition to N-terminal arginylation, ATE1 can also add arginine to the acidic side chains of Asp and Glu on the mid-chain sites of intact proteins
physiological function
the Arg/N-end rule pathway may function to actively protect cells from detrimental effects of cellular stresses, including proteotoxic protein accumulation, by positively regulating autophagic flux. Under endplasmic reticulum (ER) stress, ATE1-encoded Arg-tRNA-protein transferases carry out the N-terminal arginylation of the ER heat shock protein HSPA5 that initially targets cargo proteins, along with SQSTM1, to the autophagosome. At the late stage of autophagy, the proteasomal degradation of arginylated HSPA5 might function as a critical checkpoint for the proper progression of autophagic flux in the cells. N-terminal arginylation by ATE1 is usually sufficient for the recognition by UBR proteins and subsequent ubiquitination and degradation in the Arg/N-end rule pathway. The Arg/N-end rule-mediated autophagic flux regulator might be a direct substrate of ATE1, rather than UBR1 or UBR2
malfunction
-
impairments of arginyltransferase ATE1 are implicated in congenital heart defects, obesity, cancer, and neurodegeneration
malfunction
-
diaphragm myofibrils from enzyme-knockout mice produce an increased force compared to myofibrils from wild type
physiological function
-
N-terminal arginylation of intracellular proteins by Arg-tRNA-protein transferase is a part of the N-end rule pathway of protein degradation
physiological function
-
posttranslational arginylation mediated by arginyltransferase (ATE1) is an emerging major regulator of embryogenesis and cell physiology
physiological function
-
N-terminal arginylation by the enzyme is essential for coping with cellular stresses caused by excessive misfolded proteins
additional information
estimation of the scope and evolutionary conservation of the N-terminal arginylome, analysis to a shorter list of likely arginylation targets with likely conserved regulation across mammals, these protein targets may be highly regulated by N-terminal arginylation in vivo, overview
additional information
-
estimation of the scope and evolutionary conservation of the N-terminal arginylome, analysis to a shorter list of likely arginylation targets with likely conserved regulation across mammals, these protein targets may be highly regulated by N-terminal arginylation in vivo, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ATE1_MOUSE
516
0
59146
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
knockout of ATE1 gene in MEFs significantly reduces apoptotic rates in the presence of microbial alkaloid toxin staurosporine (STS) compared to wild-type. Similar results are observed with a different stressor, CdCl2
Y416A
-
no effect on Asp-containing substrate, but affects Glu-containing substrate
additional information
additional information
construction of a conditional mouse ATE1 knockout model (Ate1-floxed mice), phenotype, overview. Complete Ate1 knockout mice die at E12.5-E14.5 during development. Nes-Ate1 mice develope to full term and are born at the expected about 25% ratio, with the body weight and appearance at birth indistinguishable from their wild-type littermates. However, these newborn mice are visibly less active than wild-type, easily pushed away by their littermates during feeding and show no inclination to explore the environment within days after birth. These newborns exhibit dramatically reduced growth in the first days of postnatal life, likely due to their inability to compete for the mother's milk with wild-type littermates. Brain phenotypes, overview. Lack of arginylation causes defects in neurite outgrowth
additional information
-
construction of a conditional mouse ATE1 knockout model (Ate1-floxed mice), phenotype, overview. Complete Ate1 knockout mice die at E12.5-E14.5 during development. Nes-Ate1 mice develope to full term and are born at the expected about 25% ratio, with the body weight and appearance at birth indistinguishable from their wild-type littermates. However, these newborn mice are visibly less active than wild-type, easily pushed away by their littermates during feeding and show no inclination to explore the environment within days after birth. These newborns exhibit dramatically reduced growth in the first days of postnatal life, likely due to their inability to compete for the mother's milk with wild-type littermates. Brain phenotypes, overview. Lack of arginylation causes defects in neurite outgrowth
additional information
generation of Ate1 knockout mice and Ate1 knockout mouse embryonic fibroblasts, phenotypes, overview. alpha-Syn-transfected Ate1 knockout cells are treated with chloroquine and bafilomycin, the inhibitors of lysosomal degradation and autophagy previously shown to interfere with alpha-syn removal from normal cells. Neither of these treatments in Ate1 knockout leads to the expected increase in intracellular levels of alpha-syn, suggesting that neither lysosomal degradation nor autophagy contribute substantially to the removal of alpha-syn, in the absence of arginylation
additional information
-
generation of Ate1 knockout mice and Ate1 knockout mouse embryonic fibroblasts, phenotypes, overview. alpha-Syn-transfected Ate1 knockout cells are treated with chloroquine and bafilomycin, the inhibitors of lysosomal degradation and autophagy previously shown to interfere with alpha-syn removal from normal cells. Neither of these treatments in Ate1 knockout leads to the expected increase in intracellular levels of alpha-syn, suggesting that neither lysosomal degradation nor autophagy contribute substantially to the removal of alpha-syn, in the absence of arginylation
additional information
generation of ATE1-/- deletion mice. Genotyping of litter embryos at E14.5 retrieved from the ATE+/- intercross reveals no live homozygous mutants, indicating that the deletion of the ATE1 gene is lethal at midgestation. Defective neuronal-cell proliferation in the ATE1-null embryonic brain, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
a targeting vector is constructed to generate Ate1-deficient mice
mouse genomic DNA encoding Ate1 is isolated from a BAC library, Ate1-deficient mouse strains are constructed
a targeting vector is constructed to generate Ate1-deficient mice
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
Ate1 and arginylation are upregulated during stress and are responsible for cell death, stress is caused by e.g. H2O2, CdCl2, heat, high salt, or staurosporine, overview
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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Biochemistry
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Mus musculus, Mus musculus BALB/c
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An essential role of N-terminal arginylation in cardiovascular development
Science
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2002
Mus musculus
Kwon, Y.T.; Kashina, A.S.; Varshavsky, A.
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Mol. Cell. Biol.
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Homo sapiens (O95260), Homo sapiens, Mus musculus (Q9Z2A5), Mus musculus
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Mus musculus
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Mus musculus
Rai, R.; Kashina, A.
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102
10123-10128
2005
Mus musculus
Rai, R.; Wong, C.C.; Xu, T.; Leu, N.A.; Dong, D.W.; Guo, C.; McLaughlin, K.J.; Yates, J.R.; Kashina, A.
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Development
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Mus musculus (Q9Z2A5), Mus musculus
Leu, N.A.; Kurosaka, S.; Kashina, A.
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PLoS ONE
4
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Mus musculus (Q9Z2A5), Mus musculus
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PLoS ONE
4
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Mus musculus (Q9Z2A5), Mus musculus
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Proc. Natl. Acad. Sci. USA
105
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2008
Mus musculus, Saccharomyces cerevisiae
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83
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Mus musculus
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Arginyltransferase is an ATP-independent self-regulating enzyme that forms distinct functional complexes in vivo
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18
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Mus musculus
Wang, J.; Han, X.; Wong, C.C.; Cheng, H.; Aslanian, A.; Xu, T.; Leavis, P.; Roder, H.; Hedstrom, L.; Yates, J.R.; Kashina, A.
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21
331-337
2014
Mus musculus
Carpio, M.A.; Decca, M.B.; Lopez Sambrooks, C.; Durand, E.S.; Montich, G.G.; Hallak, M.E.
Calreticulin-dimerization induced by post-translational arginylation is critical for stress granules scaffolding
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45
1223-1235
2013
Mus musculus
Ribeiro, P.A.; Ribeiro, J.P.; Minozzo, F.C.; Pavlov, I.; Leu, N.A.; Kurosaka, S.; Kashina, A.; Rassier, D.E.
Contractility of myofibrils from the heart and diaphragm muscles measured with atomic force cantilevers: effects of heart-specific deletion of arginyl-tRNA-protein transferase
Int. J. Cardiol.
168
3564-3571
2013
Mus musculus
Cha-Molstad, H.; Sung, K.S.; Hwang, J.; Kim, K.A.; Yu, J.E.; Yoo, Y.D.; Jang, J.M.; Han, D.H.; Molstad, M.; Kim, J.G.; Lee, Y.J.; Zakrzewska, A.; Kim, S.H.; Kim, S.T.; Kim, S.Y.; Lee, H.G.; Soung, N.K.; Ahn, J.S.; Ciechanover, A.; Kim, B.Y.; Kwon, Y.T.
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17
917-929
2015
Mus musculus
Brower, C.S.; Rosen, C.E.; Jones, R.H.; Wadas, B.C.; Piatkov, K.I.; Varshavsky, A.
Liat1, an arginyltransferase-binding protein whose evolution among primates involved changes in the numbers of its 10-residue repeats
Proc. Natl. Acad. Sci. USA
111
E4936-E4945
2014
Mus musculus
Jiang, Y.; Lee, J.; Lee, J.; Lee, J.; Kim, J.; Choi, W.; Yoo, Y.; Cha-Molstad, H.; Kim, B.; Kwon, Y.; Noh, S.; Kim, K.; Lee, M.
The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins
Autophagy
12
2197-2212
2016
Homo sapiens (O95260), Mus musculus (Q9Z2A5)
Kim, E.; Kim, S.; Lee, J.H.; Kwon, Y.T.; Lee, M.J.
Ablation of Arg-tRNA-protein transferases results in defective neural tube development
BMB Rep.
49
443-448
2016
Mus musculus (Q9Z2A5), Mus musculus 129SvEv/C57BL/6 (Q9Z2A5)
Kumar, A.; Birnbaum, M.; Patel, D.; Morgan, W.; Singh, J.; Barrientos, A.; Zhang, F.
Posttranslational arginylation enzyme Ate1 affects DNA mutagenesis by regulating stress response
Cell Death Dis.
7
e2378
2016
Homo sapiens (O95260), Homo sapiens, Mus musculus (Q9Z2A5), Mus musculus, Saccharomyces cerevisiae, Saccharomyces cerevisiae BY4741
Wang, J.; Pavlyk, I.; Vedula, P.; Sterling, S.; Leu, N.A.; Dong, D.W.; Kashina, A.
Arginyltransferase ATE1 is targeted to the neuronal growth cones and regulates neurite outgrowth during brain development
Dev. Biol.
430
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2017
Mus musculus (Q9Z2A5), Mus musculus
Wang, J.; Han, X.; Leu, N.A.; Sterling, S.; Kurosaka, S.; Fina, M.; Lee, V.M.; Dong, D.W.; Yates, J.R.; Kashina, A.
Protein arginylation targets alpha synuclein, facilitates normal brain health, and prevents neurodegeneration
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11323
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Mus musculus (Q9Z2A5), Mus musculus
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