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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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.
i.e. HERP, a key inhibitor of the turnover and N-terminal arginylation of molecular chaperone BiP. HERP is a 43-kDa endoplasmic reticlulum (ER) membrane-integrated protein that is an essential component of ER-associated protein degradation
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-/-) HeLa cells. The direct targets of PCA are UBR1 and UBR2 proteins, not ATE1, an upstream component of the Arg/N-end rule pathway
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Breast Neoplasms
Inhibition of arginyltransferase 1 induces transcriptional activity of myocardin-related transcription factor A (MRTF-A) and promotes directional migration.
Contractility of myofibrils from the heart and diaphragm muscles measured with atomic force cantilevers: Effects of heart-specific deletion of arginyl-tRNA-protein transferase.
Contractility of myofibrils from the heart and diaphragm muscles measured with atomic force cantilevers: Effects of heart-specific deletion of arginyl-tRNA-protein transferase.
Comment on "Multiple logistic regression analysis predicts cancer risk among tobacco usage with glutathione R-transferase p1 genotyping in patients with head and neck cancer".
eukaryotic systems including Saccharomyces cerevisiae (budding yeast), mouse cells, and human cells, all contain the evolutionarily conserved ATE1 gene
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. The direct targets of PCA are UBR1 and UBR2 proteins, not ATE1, an upstream component of the Arg/N-end rule pathway
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
the molecular chaperone BiP (also known as GRP78) is short-lived under basal conditions and endoplasmic reticulum (ER) stress. The turnover of BiP is in part driven by its N-terminal arginylation (Nt-arginylation) by arginyltransferase ATE1, which generates an autophagic N-degron of the N-end rule pathway. ER stress elicits the formation of R-BiP, an effect that is increased when the proteasome is also inhibited. Nt-arginylation correlates with the cytosolic relocalization of BiP under the types of stress tested. The cytosolic relocalization of BiP does not require the functionality of the unfolded protein response or the Sec61- or Derlin1-containing translocon. A key inhibitor of the turnover and Nt-arginylation of BiP is HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation. Pharmacological inhibition of the ER-Golgi secretory pathway also suppressed R-BiP formation. Cytosolic R-BiP induced by ER stress and proteasomal inhibition is routed to autophagic vacuoles and possibly additional metabolic fates. These results suggest that Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of ER-resident proteins
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
N-terminal arginylation (Nt-arginylation) is a posttranslational modification for which the amino acid L-Arg is conjugated to the Nt-Asp or Nt-Glu residues by ATE1-encoded R-transferases. Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of endoplasmic reticulum (ER)-resident proteins. A set of ER-residing molecular chaperones, such as BiP, calreticulin, and PDI, are N-terminally arginylated by enzyme ATE1. Nt-arginylation of BiP is induced in response to cytosolic double-stranded DNA, leading to the cytosolic accumulation of Nt-arginylated BiP, R-BiP. The Nt-Arg residue of R-BiP binds p62 (also known as SQSTM1 and Sequestosome-1) and subsequently is delivered to the autophagosomes for lysosomal degradation. Nt-arginylation mediates the cytosolic relocalization of BiP independently of the functionality of the ERAD core machinery
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
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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
Alternative splicing results in differential expression, activity, and localization of the two forms of arginyl-tRNA-protein transferase, a component of the N-end rule pathway
Mol. Cell. Biol.
19
182-193
1999
Homo sapiens (O95260), Homo sapiens, Mus musculus (Q9Z2A5), Mus musculus