UniProt functional annotation for P07814



	UniProt functional annotation for P07814

UniProt code: P07814.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Multifunctional protein which is primarily part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex, that catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA (PubMed:1756734, PubMed:24100331, PubMed:23263184). The phosphorylation of EPRS1, induced by interferon-gamma, dissociates the protein from the aminoacyl-tRNA synthetase multienzyme complex and recruits it to the GAIT complex that binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin), suppressing their translation. Interferon-gamma can therefore redirect, in specific cells, the EPRS1 function from protein synthesis to translation inhibition (PubMed:15479637, PubMed:23071094). Also functions as an effector of the mTORC1 signaling pathway by promoting, through SLC27A1, the uptake of long-chain fatty acid by adipocytes. Thereby, it also plays a role in fat metabolism and more indirectly influences lifespan (PubMed:28178239). {ECO:0000269|PubMed:15479637, ECO:0000269|PubMed:1756734, ECO:0000269|PubMed:23071094, ECO:0000269|PubMed:23263184, ECO:0000269|PubMed:24100331, ECO:0000269|PubMed:28178239}.

Catalytic activity: Reaction=ATP + L-glutamate + tRNA(Glu) = AMP + diphosphate + L- glutamyl-tRNA(Glu); Xref=Rhea:RHEA:23540, Rhea:RHEA-COMP:9663, Rhea:RHEA-COMP:9680, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:78442, ChEBI:CHEBI:78520, ChEBI:CHEBI:456215; EC=6.1.1.17;

Catalytic activity: Reaction=ATP + L-proline + tRNA(Pro) = AMP + diphosphate + L-prolyl- tRNA(Pro); Xref=Rhea:RHEA:14305, Rhea:RHEA-COMP:9700, Rhea:RHEA- COMP:9702, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:60039, ChEBI:CHEBI:78442, ChEBI:CHEBI:78532, ChEBI:CHEBI:456215; EC=6.1.1.15; Evidence={ECO:0000269|PubMed:23263184, ECO:0000269|PubMed:24100331};

Activity regulation: Inhibited by halofuginone. {ECO:0000269|PubMed:23263184, ECO:0000269|PubMed:24100331}.

Subunit: Homodimer (PubMed:24100331, PubMed:23263184). Part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex (MSC), that is composed of the tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:24312579, PubMed:19131329, PubMed:19289464). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex (PubMed:26472928). Interacts with TARS3 (PubMed:24312579). Interacts with DUS2L (PubMed:15994936). Component of the GAIT complex which is composed of EPRS1, RPL13A and GAPDH. For human, the complex assembly seems to be a two-step process in which EPRS1 first associates with SYNCRIP to form a pre-GAIT complex which is deficient in GAIT element binding (PubMed:15479637). Interacts (phosphorylated at Ser-999) with SLC27A1; mediates the translocation of SLC27A1 from the cytoplasm to the plasma membrane thereby increasing the uptake of long-chain fatty acids (PubMed:28178239). {ECO:0000269|PubMed:15479637, ECO:0000269|PubMed:15994936, ECO:0000269|PubMed:19131329, ECO:0000269|PubMed:19289464, ECO:0000269|PubMed:19647514, ECO:0000269|PubMed:23263184, ECO:0000269|PubMed:24100331, ECO:0000269|PubMed:24312579, ECO:0000269|PubMed:26472928, ECO:0000269|PubMed:28178239}.

Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:10791971, ECO:0000269|PubMed:19289464}. Membrane {ECO:0000269|PubMed:28178239}; Peripheral membrane protein {ECO:0000305|PubMed:19289464, ECO:0000305|PubMed:28178239}. Note=Translocates from cytosol to membranes upon phosphorylation at Ser-999. {ECO:0000269|PubMed:19289464, ECO:0000269|PubMed:28178239}.

Domain: The WHEP-TRS domains are involved in RNA binding. {ECO:0000250|UniProtKB:Q7SIA2}.

Ptm: Phosphorylated at Ser-886 by CDK5 (PubMed:19647514, PubMed:21220307). Phosphorylated at Ser-999 by RPS6KB1; triggers EPRS1 release from the aminoacyl-tRNA synthetase multienzyme complex (PubMed:19647514, PubMed:21220307, PubMed:28178239). In monocytes, the IFN-gamma-induced sequential phosphorylation at Ser-886 and Ser-999 releases EPRS1 from the aminoacyl-tRNA synthetase multienzyme complex, allowing its association with the GAIT complex. Phosphorylation at Ser- 999 is specifically required for the RPL13A-mediated interaction of the GAIT complex with eIF4G (PubMed:19647514, PubMed:21220307). Phosphorylation at Ser-999 by RPS6KB1, is also induced by insulin through activation of the mTORC1 signaling pathway and promotes the interaction of EPRS1 with SLC27A1 (PubMed:28178239). {ECO:0000269|PubMed:19647514, ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:28178239}.

Disease: Leukodystrophy, hypomyelinating, 15 (HLD15) [MIM:617951]: An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with thinning of the corpus callosum. Clinical features include motor and cognitive impairment appearing in the first or second decade of life, dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. {ECO:0000269|PubMed:29576217}. Note=The disease may be caused by variants affecting the gene represented in this entry.

Similarity: In the N-terminal section; belongs to the class-I aminoacyl-tRNA synthetase family. Glutamate--tRNA ligase type 2 subfamily. {ECO:0000305}.

Similarity: In the C-terminal section; belongs to the class-II aminoacyl-tRNA synthetase family. {ECO:0000305}.

Sequence caution: Sequence=AAH15494.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH34797.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH46156.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH58921.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAS72877.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=CAA30354.1; Type=Miscellaneous discrepancy; Note=Sequencing errors.; Evidence={ECO:0000305}; Sequence=CAA38224.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Multifunctional protein which is primarily part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex, that catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA (PubMed:1756734, PubMed:24100331, PubMed:23263184). The phosphorylation of EPRS1, induced by interferon-gamma, dissociates the protein from the aminoacyl-tRNA synthetase multienzyme complex and recruits it to the GAIT complex that binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin), suppressing their translation. Interferon-gamma can therefore redirect, in specific cells, the EPRS1 function from protein synthesis to translation inhibition (PubMed:15479637, PubMed:23071094). Also functions as an effector of the mTORC1 signaling pathway by promoting, through SLC27A1, the uptake of long-chain fatty acid by adipocytes. Thereby, it also plays a role in fat metabolism and more indirectly influences lifespan (PubMed:28178239). {ECO:0000269\|PubMed:15479637, ECO:0000269\|PubMed:1756734, ECO:0000269\|PubMed:23071094, ECO:0000269\|PubMed:23263184, ECO:0000269\|PubMed:24100331, ECO:0000269\|PubMed:28178239}.


Catalytic activity:		Reaction=ATP + L-glutamate + tRNA(Glu) = AMP + diphosphate + L- glutamyl-tRNA(Glu); Xref=Rhea:RHEA:23540, Rhea:RHEA-COMP:9663, Rhea:RHEA-COMP:9680, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:78442, ChEBI:CHEBI:78520, ChEBI:CHEBI:456215; EC=6.1.1.17;
Catalytic activity:		Reaction=ATP + L-proline + tRNA(Pro) = AMP + diphosphate + L-prolyl- tRNA(Pro); Xref=Rhea:RHEA:14305, Rhea:RHEA-COMP:9700, Rhea:RHEA- COMP:9702, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:60039, ChEBI:CHEBI:78442, ChEBI:CHEBI:78532, ChEBI:CHEBI:456215; EC=6.1.1.15; Evidence={ECO:0000269\|PubMed:23263184, ECO:0000269\|PubMed:24100331};
Activity regulation:		Inhibited by halofuginone. {ECO:0000269\|PubMed:23263184, ECO:0000269\|PubMed:24100331}.
Subunit:		Homodimer (PubMed:24100331, PubMed:23263184). Part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex (MSC), that is composed of the tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:24312579, PubMed:19131329, PubMed:19289464). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex (PubMed:26472928). Interacts with TARS3 (PubMed:24312579). Interacts with DUS2L (PubMed:15994936). Component of the GAIT complex which is composed of EPRS1, RPL13A and GAPDH. For human, the complex assembly seems to be a two-step process in which EPRS1 first associates with SYNCRIP to form a pre-GAIT complex which is deficient in GAIT element binding (PubMed:15479637). Interacts (phosphorylated at Ser-999) with SLC27A1; mediates the translocation of SLC27A1 from the cytoplasm to the plasma membrane thereby increasing the uptake of long-chain fatty acids (PubMed:28178239). {ECO:0000269\|PubMed:15479637, ECO:0000269\|PubMed:15994936, ECO:0000269\|PubMed:19131329, ECO:0000269\|PubMed:19289464, ECO:0000269\|PubMed:19647514, ECO:0000269\|PubMed:23263184, ECO:0000269\|PubMed:24100331, ECO:0000269\|PubMed:24312579, ECO:0000269\|PubMed:26472928, ECO:0000269\|PubMed:28178239}.
Subcellular location:		Cytoplasm, cytosol {ECO:0000269\|PubMed:10791971, ECO:0000269\|PubMed:19289464}. Membrane {ECO:0000269\|PubMed:28178239}; Peripheral membrane protein {ECO:0000305\|PubMed:19289464, ECO:0000305\|PubMed:28178239}. Note=Translocates from cytosol to membranes upon phosphorylation at Ser-999. {ECO:0000269\|PubMed:19289464, ECO:0000269\|PubMed:28178239}.
Domain:		The WHEP-TRS domains are involved in RNA binding. {ECO:0000250\|UniProtKB:Q7SIA2}.
Ptm:		Phosphorylated at Ser-886 by CDK5 (PubMed:19647514, PubMed:21220307). Phosphorylated at Ser-999 by RPS6KB1; triggers EPRS1 release from the aminoacyl-tRNA synthetase multienzyme complex (PubMed:19647514, PubMed:21220307, PubMed:28178239). In monocytes, the IFN-gamma-induced sequential phosphorylation at Ser-886 and Ser-999 releases EPRS1 from the aminoacyl-tRNA synthetase multienzyme complex, allowing its association with the GAIT complex. Phosphorylation at Ser- 999 is specifically required for the RPL13A-mediated interaction of the GAIT complex with eIF4G (PubMed:19647514, PubMed:21220307). Phosphorylation at Ser-999 by RPS6KB1, is also induced by insulin through activation of the mTORC1 signaling pathway and promotes the interaction of EPRS1 with SLC27A1 (PubMed:28178239). {ECO:0000269\|PubMed:19647514, ECO:0000269\|PubMed:21220307, ECO:0000269\|PubMed:28178239}.
Disease:		Leukodystrophy, hypomyelinating, 15 (HLD15) [MIM:617951]: An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with thinning of the corpus callosum. Clinical features include motor and cognitive impairment appearing in the first or second decade of life, dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. {ECO:0000269\|PubMed:29576217}. Note=The disease may be caused by variants affecting the gene represented in this entry.
Similarity:		In the N-terminal section; belongs to the class-I aminoacyl-tRNA synthetase family. Glutamate--tRNA ligase type 2 subfamily. {ECO:0000305}.
Similarity:		In the C-terminal section; belongs to the class-II aminoacyl-tRNA synthetase family. {ECO:0000305}.
Sequence caution:		Sequence=AAH15494.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH34797.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH46156.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAH58921.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; Sequence=AAS72877.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=CAA30354.1; Type=Miscellaneous discrepancy; Note=Sequencing errors.; Evidence={ECO:0000305}; Sequence=CAA38224.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};