2.3.2.8	evolution	arginyltransferase (ATE1) is an evolutionary conserved enzyme	760135	
2.3.2.8	evolution	ATE1 Arg-transferase is an evolutionarily conserved protein present in all eukaryotes from fungi to animals	-, 758964	
2.3.2.8	evolution	eukaryotic systems including Saccharomyces cerevisiae (budding yeast), mouse cells, and human cells, all contain the evolutionarily conserved ATE1 gene	-, 759021	
2.3.2.8	evolution	plant ATEs and their evolutionary relationship with other ATEs, overview. Identification of two Arabidopsis thaliana Nt-amidases mediating recognition of tertiary destabilizing Nt-amino acids Asn and Gln have shown that the N-end rule pathway in plants is very similar to that in animals, highlighting a possible evolutionary common origin. But the steps related to protein degradation likely evolved after plant and animal divergence, as suggested by the differences in PRTs and UBR N-recognins. Plant evolutionary analysis has identified ATE orthologous genes from the green alga Chlamydomonas reinhardtii to angiosperms. In general, only one ATE gene is detected in a given plant species, with the two conserved ATE domains located at the N- and C-termini. Some species, such as Arabidopsis, Populus, and Sorghum, have experienced gene duplication	759302	
2.3.2.8	evolution	the Dictyostelium discoideum genome encodes only one Ate1 family member, Ate1 (DdAte1)	-, 759753	
2.3.2.8	malfunction	Ate1- null cells are almost completely lacking focal actin adhesion sites at the substrate-attached surface and are only weakly adhesive. In vitro polymerization assays with actin purified from ate1-null cells reveal a diminished polymerization capacity in comparixadson to wild-type actin. Chemotaxis of aggregation-competent ate1-/- null cells is impaired in three-dimensional compared with two-dimensional environments	-, 759753	
2.3.2.8	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	-, 758964	
2.3.2.8	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	758714	
2.3.2.8	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. The direct targets of PCA are UBR1 and UBR2 proteins, not ATE1, an upstream component of the Arg/N-end rule pathway	758714	
2.3.2.8	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	759108	
2.3.2.8	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	760145	
2.3.2.8	malfunction	deletion or downregulation of the ATE1 gene disrupts typical stress responses by bypassing growth arrest and suppressing cell death events in the presence of disease-related stressing factors, including oxidative, heat, and osmotic stresses, as well as the exposure to heavy metals or radiation. Conversely, in wild-type cells responding to stress, there is an increase of cellular Ate1 protein level and arginylation activity. The faster growth rates of ate1DELTA mutant yeast in stressing condition compared to wild-type is likely caused by a lack of growth arrest	-, 759021	
2.3.2.8	malfunction	diaphragm myofibrils from enzyme-knockout mice produce an increased force compared to myofibrils from wild type	736259	
2.3.2.8	malfunction	impairments of arginyltransferase ATE1 are implicated in congenital heart defects, obesity, cancer, and neurodegeneration	718803	
2.3.2.8	malfunction	knockdown of arginyltransferase ATE1 attenuates cardiac hypertrophy and fibrosis in vitro and in vivo through the TAK1-JNK1/2 pathway. The cardioprotective role of ATE1 silencing is mediated by the interruption of TAK1 activity-dependent JNK1/2 signaling pathway. The MAPK signaling cascade is one of the signaling pathways involved in cardiac hypertrophy. ATE1 knockdown in presence of cardiac stress performs a cardioprotective action. Cardiac ATE1 deficiency restores cardiac dysfunction after right renal artery ligation. Phenotype, overview	760135	
2.3.2.8	malfunction	knockdown of ATE1 does not significantly influence the mRNA expression of unfolded protein response (UPR) proteins, BiP, CHOP, and ATF4	760187	
2.3.2.8	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	759021	
2.3.2.8	malfunction	RAP2.12 stabilization in ate1 ate2 double-null mutant plant lines implicates ATE1 as an ERF-VII-targeting arginyl transferase in vivo	759833	
2.3.2.8	malfunction	the relative abundance of methylesterase 10 (MES10), nucleoside diphosphate kinase family protein (NDPK1), and two asparagine synthetases (ASNs) is augmented in ate1/ate2 mutants. Disrupted ATE1 in dls1 mutants shows an extremely slow age-dependent, dark-induced leaf senescence, phenotype. Double mutant for AtATE1 and AtATE2 (ate1.ate2) displays lost sensitivity to hormone abscisic acid and consequently uncontrolled seed germination and establishment. Arabidopsis ate1/ate2 or prt6 mutants cannot degrade ERFVII, and as a consequence show increased expression of hypoxia-responsive genes involved in fermentation and sugar consumption even under oxygen-rich conditions	759302	
2.3.2.8	metabolism	link between Ate1 and a variety of diseases including cancer	-, 759021	
2.3.2.8	metabolism	regulation of protein stability and/or degradation of misfolded and damaged proteins are essential cellular processes. A part of this regulation is mediated by the so-called N-end rule proteolytic pathway, which, in concert with the ubiquitin proteasome system (UPS), drives protein degradation depending on the N-terminal amino acid sequence. One important enzyme involved in this process is arginyl-t-RNA transferase, known as ATE. Great importance of the ATE/N-end rule pathway in regulating plant signaling. Plant development, seed germination, leaf morphology and responses to gas signaling in plants are among the processes affected by the ATE/N-end rule pathway. A signaling pathways in plants controlled by arginylation is that involving the ethylene responsive transcription factor VII (ERFVII)	759302	
2.3.2.8	metabolism	regulation of protein stability and/or degradation of misfolded and damaged proteins are essential cellular processes. A part of this regulation is mediated by the so-called N-end rule proteolytic pathway, which, in concert with the ubiquitin proteasome system (UPS), drives protein degradation depending on the N-terminal amino acid sequence. One important enzyme involved in this process is arginyl-t-RNA transferase, known as ATE. Great importance of the ATE/N-end rule pathway in regulating plant signaling. Plant development, seed germination, leaf morphology and responses to gas signaling in plants are among the processes affected by the ATE/N-end rule pathway. The N-recognin E3 ligase PRT6 and AtATE1 and AtATE2 are involved in seed germination controlled by abscisic acid. A signaling pathways in plants controlled by arginylation is that involving the ethylene responsive transcription factor VII (ERFVII)	759302	
2.3.2.8	metabolism	submergence-induced hypoxia in plants (e.g. flooded plants) results in stabilization of group VII ethylene response factors (ERF-VIIs), which aid survival under these adverse conditions. ERF-VII stability is controlled by the N-end rule pathway, which proposes that ERF-VII N-terminal cysteine oxidation in normoxia enables arginylation followed by proteasomal degradation. The plant cysteine oxidases (PCOs) are identified as catalysts of this oxidation. ERF-VII stabilization in hypoxia presumably arises from reduced PCO activity. PCO dioxygenase activity produces Cys-sulfinic acid at the N-terminus of an ERF-VII peptide, which then undergoes efficient arginylation by an arginyl transferase (ATE1). This provides molecular evidence of N-terminal Cys-sulfinic acid formation and arginylation by N-end rule pathway components, and a substrate of ATE1 in plants. PCOs catalyse dioxygenation of the ERF-VII peptides RAP2_2 to RAP2_11	759833	
2.3.2.8	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	-, 758964	
2.3.2.8	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	758714	
2.3.2.8	metabolism	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	760187	
2.3.2.8	additional information	ATE protein sequences contain two Pfam domains named ATE-N (PF04376) and ATE-C (PF04377), which are located at N- and C-termini, respectively	759302	
2.3.2.8	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	760164	
2.3.2.8	additional information	GFP-tagged Ate1 rapidly relocates to sites of newly formed actin-rich protrusions	-, 759753	
2.3.2.8	additional information	identification of targets and interaction partners, e.g. sHSP17.2a chaperone, of arginyl-tRNA protein transferase (ATE) in the model plant Physcomitrella patens by mass spectrometry, employing two different immunoaffinity strategies and a recently established transgenic ATE:GUS reporter line. A commercially available antibody against the fused reporter protein (beta-glucuronidase) to pull down ATE and its interacting proteins. Preparation of specific antibodies and immunoprecipitation of arginylated proteins, overview. Arginylated peptides are reliably identified for three different proteins namely acylamino-acid releasing enzyme (PpAARE, Pp1s619_3V6.1), an uncharacterized protein (UP, Pp1s68_62V6.1) and a putative AAA-type ATPase (PpATAD3.1, Pp1s106_174V6.1), and for one additional protein, an ABC transporter family protein (PpABCB20, Pp1s29_108V6.1). The identified arginylation do not represent a side-chain arginylation as the a1 ion of a dimethylated arginine is present in the corresponding HCD spectrum	759770	
2.3.2.8	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	-, 759021	
2.3.2.8	physiological function	arginyltransferase ATE1 can modulate the hypertrophic growth of myocytes induced by Ang II. Physiological importance of ATE1 in higher eukaryotes	760135	
2.3.2.8	physiological function	arginyltransferases (ATE) mediates N-terminal arginylation of secondary destabilizing residues (D, E, Cox)	759770	
2.3.2.8	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	-, 758964	
2.3.2.8	physiological function	Ate1 plays a role in the regulation of cytoskeleton and is essential for cardiovascular development and angiogenesis	706443	
2.3.2.8	physiological function	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	760187	
2.3.2.8	physiological function	N-terminal arginylation by the enzyme is essential for coping with cellular stresses caused by excessive misfolded proteins	736857	
2.3.2.8	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	706444, 706498	
2.3.2.8	physiological function	PCO dioxygenase activity produces Cys-sulfinic acid at the N-terminus of an ERF-VII peptide, which then undergoes efficient arginylation by an arginyl transferase (ATE1). This provides molecular evidence of N-terminal Cys-sulfinic acid formation and arginylation by N-end rule pathway components, and a substrate of ATE1 in plants. Proposed arginylation requirements for the Arg/Cys branch of the N-end rule pathway	759833	
2.3.2.8	physiological function	posttranslational arginylation mediated by arginyltransferase (ATE1) is an emerging major regulator of embryogenesis and cell physiology	718803	
2.3.2.8	physiological function	posttranslational arginylation mediated by Ate1 is essential for cardiovascular development and angiogenesis and directly affects the myocardium structure in the developing heart	703373	
2.3.2.8	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	760145	
2.3.2.8	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	759108	
2.3.2.8	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	760164	
2.3.2.8	physiological function	regulation of protein stability and/or degradation of misfolded and damaged proteins are essential cellular processes, proposed model of biological processes regulated by ATE arginylation in plants, overview. A part of this regulation is mediated by the so-called N-end rule proteolytic pathway, which, in concert with the ubiquitin proteasome system (UPS), drives protein degradation depending on the N-terminal amino acid sequence. One important enzyme involved in this process is arginyl-t-RNA transferase, known as ATE. This enzyme acts post-translationally by introducing an arginine residue at the N-terminus of specific protein targets to signal degradation via the UPS. Biological functions of plant ATE proteins, overview. Asp, Glu or oxidized Cys are ATE substrates, and the protein may become a substrate for E3 ligases following arginylation	759302	
2.3.2.8	physiological function	regulation of protein stability and/or degradation of misfolded and damaged proteins are essential cellular processes, proposed model of biological processes regulated by ATE arginylation in plants, overview. A part of this regulation is mediated by the so-called N-end rule proteolytic pathway, which, in concert with the ubiquitin proteasome system (UPS), drives protein degradation depending on the N-terminal amino acid sequence. One important enzyme involved in this process is arginyl-t-RNA transferase, known as ATE. This enzyme acts post-translationally by introducing an arginine residue at the N-terminus of specific protein targets to signal degradation via the UPS. Biological functions of plant ATE proteins, overview. Asp, Glu, or oxidized Cys are ATE substrates, and the protein may become a substrate for E3 ligases following arginylation	759302	
2.3.2.8	physiological function	regulation of protein stability and/or degradation of misfolded and damaged proteins are essential cellular processes, proposed model of biological processes regulated by ATE arginylation in plants, overview. A part of this regulation is mediated by the so-called N-end rule proteolytic pathway, which, in concert with the ubiquitin proteasome system (UPS), drives protein degradation depending on the N-terminal amino acid sequence. One important enzyme involved in this process is arginyl-t-RNA transferase, known as ATE. This enzyme acts post-translationally by introducing an arginine residue at the N-terminus of specific protein targets to signal degradation via the UPS. Biological functions of plant ATE proteins, overview. Asp, Glu, or oxidized Cys are ATE substrates, and the protein may become a substrate for E3 ligases following arginylation. In plants, ATE is not required for viability	759302	
2.3.2.8	physiological function	regulation of protein stability and/or degradation of misfolded and damaged proteins are essential cellular processes, proposed model of biological processes regulated by ATE arginylation in plants, overview. A part of this regulation is mediated by the so-called N-end rule proteolytic pathway, which, in concert with the ubiquitin proteasome system (UPS), drives protein degradation depending on the N-terminal amino acid sequence. One important enzyme involved in this process is arginyl-t-RNA transferase, known as ATE. This enzyme acts post-translationally by introducing an arginine residue at the N-terminus of specific protein targets to signal degradation via the UPS. Biological functions of plant ATE proteins, overview. Asp, Glu, or oxidized Cys are ATE substrates, and the protein may become a substrate for E3 ligases following arginylation. In plants, ATE is not required for viability. The arginylation branch of the N-end rule pathway is also responsible for repressing expression of the meristempromoting brevipedicellus (BP) gene during leaf development, acting in a redundant way with the asymmetric leaves 1 (AS1) transcription factor complex, a known negative regulator of BP expression	759302	
2.3.2.8	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	758714	
2.3.2.8	physiological function	the enzyme is essential for tumor suppression and also participates in suppression of metastatic growth	736911	
2.3.2.8	physiological function	the highly conserved enzyme arginyl-tRNA-protein transferase (Ate1) mediates arginylation, a posttranslational modification that is only incompletely understood at its molexadcular level. Ate1-mediated posttranslational arginylation affects substrate adhesion and cell migration in Dictyostelium discoideum. Arginylation plays a crucial role in the regulation of cytoskeletal activities	-, 759753