UniProt functional annotation for P41250



	UniProt functional annotation for P41250

UniProt code: P41250.

Organism: Homo sapiens (Human).

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

Function: Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017). {ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:19710017, ECO:0000269|PubMed:24898252, ECO:0000269|PubMed:28675565}.

Catalytic activity: Reaction=ATP + glycine + tRNA(Gly) = AMP + diphosphate + glycyl- tRNA(Gly); Xref=Rhea:RHEA:16013, Rhea:RHEA-COMP:9664, Rhea:RHEA- COMP:9683, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57305, ChEBI:CHEBI:78442, ChEBI:CHEBI:78522, ChEBI:CHEBI:456215; EC=6.1.1.14; Evidence={ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:24898252, ECO:0000269|PubMed:28675565}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16014; Evidence={ECO:0000305|PubMed:24898252};

Catalytic activity: Reaction=2 ATP + H(+) = diphosphate + P(1),P(4)-bis(5'-adenosyl) tetraphosphate; Xref=Rhea:RHEA:34935, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58141; Evidence={ECO:0000269|PubMed:19710017}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:34936; Evidence={ECO:0000305|PubMed:19710017};

Activity regulation: Ap4A synthesis is inhibited by tRNA, via the disruption of the second ATP-binding site by direct blocking and/or by tRNA-induced conformational change. {ECO:0000269|PubMed:19710017}.

Biophysicochemical properties: Kinetic parameters: KM=1.3 uM for tRNA(Gly(GCC)) {ECO:0000269|PubMed:17544401}; KM=15 uM for glycine {ECO:0000269|PubMed:17544401}; KM=0.74 uM for tRNA(Gly) {ECO:0000269|PubMed:28675565}; Note=kcat is 0.049 sec(-1) for aminoacylation of tRNA(Gly). {ECO:0000269|PubMed:28675565};

Subunit: Homodimer. {ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:17545306, ECO:0000305|PubMed:19710017, ECO:0000305|PubMed:24898252}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:17035524}. Cell projection, axon {ECO:0000269|PubMed:17035524}. Secreted {ECO:0000250|UniProtKB:Q9CZD3}. Secreted, extracellular exosome {ECO:0000250|UniProtKB:Q9CZD3}. Note=In transfected COS7 cells, not detected in mitochondria, nor in Golgi apparatus (PubMed:17035524). Secreted by motor neuron, possibly through the exosome pathway (By similarity). {ECO:0000250|UniProtKB:Q9CZD3, ECO:0000269|PubMed:17035524}.

Subcellular location: [Isoform 1]: Mitochondrion {ECO:0000269|PubMed:17529987, ECO:0000269|PubMed:26327585}. Cytoplasm {ECO:0000269|PubMed:26327585}.

Subcellular location: [Isoform 2]: Cytoplasm {ECO:0000269|PubMed:17529987, ECO:0000269|PubMed:26327585}. Cell projection, axon {ECO:0000269|PubMed:25168514}.

Tissue specificity: Widely expressed, including in brain and spinal cord. {ECO:0000269|PubMed:12690580}.

Tissue specificity: [Isoform 2]: Expressed in brain, spinal cord, muscle, heart and spleen. {ECO:0000269|PubMed:26327585}.

Tissue specificity: [Isoform 1]: Expressed in brain, spinal cord, muscle, heart, spleen and liver. {ECO:0000269|PubMed:26327585}.

Disease: Charcot-Marie-Tooth disease 2D (CMT2D) [MIM:601472]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:12690580, ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:17101916, ECO:0000269|PubMed:17663003, ECO:0000269|PubMed:20169446, ECO:0000269|PubMed:24604904, ECO:0000269|PubMed:25168514, ECO:0000269|PubMed:26244500, ECO:0000269|PubMed:26503042}. Note=The disease is caused by variants affecting the gene represented in this entry. Contrary to the wild-type protein, CMT2D variants Gly-125 and Arg-294 strongly interact with NRP1. This interaction may compete out VEGFA binding and inhibits VEGFA-NRP1 signling which is essential for motor neuron survival, as suggested by experiments done in a mouse model. {ECO:0000269|PubMed:26503042}.

Disease: Neuronopathy, distal hereditary motor, 5A (HMN5A) [MIM:600794]: A disorder characterized by distal muscular atrophy mainly affecting the upper extremities, in contrast to other distal motor neuronopathies. These constitute a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:12690580, ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:23279345, ECO:0000269|PubMed:24627108, ECO:0000269|PubMed:26503042}. Note=The disease is caused by variants affecting the gene represented in this entry. Contrary to the wild-type protein, HMN5A variant Pro-183 strongly interacts with NRP1. This interaction may compete out VEGFA binding and inhibits VEGFA-NRP1 signling which is essential for motor neuron survival, as suggested by experiments done in a mouse model. {ECO:0000269|PubMed:26503042}.

Miscellaneous: Human GlyRS uses direct ATP condensation to synthesize Ap4A, a unique amino acid-independent mechanism, in contrast to the classical amino acid-dependent mechanism for synthesis of Ap4A by a tRNA synthetase, that involves the generation of an enzyme-bound aminoacyl-AMP which is then attacked by ATP to form Ap4A. {ECO:0000269|PubMed:19710017}.

Miscellaneous: [Isoform 2]: The isoform 2 translation is regulated by an Internal Ribosome Entry Site (IRES) and an upstream Open Reading Frame. Both are important in hindering the synthesis of the mitochondrial GARS and target the translation of the cytosolic enzyme to ER-bound ribosomes. {ECO:0000305|PubMed:26327585}.

Similarity: Belongs to the class-II aminoacyl-tRNA synthetase family. {ECO:0000305}.

Sequence caution: Sequence=AAA57001.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=AAA86443.1; 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:		Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017). {ECO:0000269\|PubMed:17544401, ECO:0000269\|PubMed:19710017, ECO:0000269\|PubMed:24898252, ECO:0000269\|PubMed:28675565}.


Catalytic activity:		Reaction=ATP + glycine + tRNA(Gly) = AMP + diphosphate + glycyl- tRNA(Gly); Xref=Rhea:RHEA:16013, Rhea:RHEA-COMP:9664, Rhea:RHEA- COMP:9683, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57305, ChEBI:CHEBI:78442, ChEBI:CHEBI:78522, ChEBI:CHEBI:456215; EC=6.1.1.14; Evidence={ECO:0000269\|PubMed:17544401, ECO:0000269\|PubMed:24898252, ECO:0000269\|PubMed:28675565}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16014; Evidence={ECO:0000305\|PubMed:24898252};
Catalytic activity:		Reaction=2 ATP + H(+) = diphosphate + P(1),P(4)-bis(5'-adenosyl) tetraphosphate; Xref=Rhea:RHEA:34935, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58141; Evidence={ECO:0000269\|PubMed:19710017}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:34936; Evidence={ECO:0000305\|PubMed:19710017};
Activity regulation:		Ap4A synthesis is inhibited by tRNA, via the disruption of the second ATP-binding site by direct blocking and/or by tRNA-induced conformational change. {ECO:0000269\|PubMed:19710017}.
Biophysicochemical properties:		Kinetic parameters: KM=1.3 uM for tRNA(Gly(GCC)) {ECO:0000269\|PubMed:17544401}; KM=15 uM for glycine {ECO:0000269\|PubMed:17544401}; KM=0.74 uM for tRNA(Gly) {ECO:0000269\|PubMed:28675565}; Note=kcat is 0.049 sec(-1) for aminoacylation of tRNA(Gly). {ECO:0000269\|PubMed:28675565};
Subunit:		Homodimer. {ECO:0000269\|PubMed:17544401, ECO:0000269\|PubMed:17545306, ECO:0000305\|PubMed:19710017, ECO:0000305\|PubMed:24898252}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:17035524}. Cell projection, axon {ECO:0000269\|PubMed:17035524}. Secreted {ECO:0000250\|UniProtKB:Q9CZD3}. Secreted, extracellular exosome {ECO:0000250\|UniProtKB:Q9CZD3}. Note=In transfected COS7 cells, not detected in mitochondria, nor in Golgi apparatus (PubMed:17035524). Secreted by motor neuron, possibly through the exosome pathway (By similarity). {ECO:0000250\|UniProtKB:Q9CZD3, ECO:0000269\|PubMed:17035524}.
Subcellular location:		[Isoform 1]: Mitochondrion {ECO:0000269\|PubMed:17529987, ECO:0000269\|PubMed:26327585}. Cytoplasm {ECO:0000269\|PubMed:26327585}.
Subcellular location:		[Isoform 2]: Cytoplasm {ECO:0000269\|PubMed:17529987, ECO:0000269\|PubMed:26327585}. Cell projection, axon {ECO:0000269\|PubMed:25168514}.
Tissue specificity:		Widely expressed, including in brain and spinal cord. {ECO:0000269\|PubMed:12690580}.
Tissue specificity:		[Isoform 2]: Expressed in brain, spinal cord, muscle, heart and spleen. {ECO:0000269\|PubMed:26327585}.
Tissue specificity:		[Isoform 1]: Expressed in brain, spinal cord, muscle, heart, spleen and liver. {ECO:0000269\|PubMed:26327585}.
Disease:		Charcot-Marie-Tooth disease 2D (CMT2D) [MIM:601472]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269\|PubMed:12690580, ECO:0000269\|PubMed:17035524, ECO:0000269\|PubMed:17101916, ECO:0000269\|PubMed:17663003, ECO:0000269\|PubMed:20169446, ECO:0000269\|PubMed:24604904, ECO:0000269\|PubMed:25168514, ECO:0000269\|PubMed:26244500, ECO:0000269\|PubMed:26503042}. Note=The disease is caused by variants affecting the gene represented in this entry. Contrary to the wild-type protein, CMT2D variants Gly-125 and Arg-294 strongly interact with NRP1. This interaction may compete out VEGFA binding and inhibits VEGFA-NRP1 signling which is essential for motor neuron survival, as suggested by experiments done in a mouse model. {ECO:0000269\|PubMed:26503042}.
Disease:		Neuronopathy, distal hereditary motor, 5A (HMN5A) [MIM:600794]: A disorder characterized by distal muscular atrophy mainly affecting the upper extremities, in contrast to other distal motor neuronopathies. These constitute a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269\|PubMed:12690580, ECO:0000269\|PubMed:17035524, ECO:0000269\|PubMed:23279345, ECO:0000269\|PubMed:24627108, ECO:0000269\|PubMed:26503042}. Note=The disease is caused by variants affecting the gene represented in this entry. Contrary to the wild-type protein, HMN5A variant Pro-183 strongly interacts with NRP1. This interaction may compete out VEGFA binding and inhibits VEGFA-NRP1 signling which is essential for motor neuron survival, as suggested by experiments done in a mouse model. {ECO:0000269\|PubMed:26503042}.
Miscellaneous:		Human GlyRS uses direct ATP condensation to synthesize Ap4A, a unique amino acid-independent mechanism, in contrast to the classical amino acid-dependent mechanism for synthesis of Ap4A by a tRNA synthetase, that involves the generation of an enzyme-bound aminoacyl-AMP which is then attacked by ATP to form Ap4A. {ECO:0000269\|PubMed:19710017}.
Miscellaneous:		[Isoform 2]: The isoform 2 translation is regulated by an Internal Ribosome Entry Site (IRES) and an upstream Open Reading Frame. Both are important in hindering the synthesis of the mitochondrial GARS and target the translation of the cytosolic enzyme to ER-bound ribosomes. {ECO:0000305\|PubMed:26327585}.
Similarity:		Belongs to the class-II aminoacyl-tRNA synthetase family. {ECO:0000305}.
Sequence caution:		Sequence=AAA57001.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=AAA86443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};