DARS2 encodes the nuclear-encoded mitochondrial aspartate-tRNA ligase (mt-AspRS), a homodimeric bacterial-type class II aminoacyl-tRNA synthetase. Imported into mitochondria via an N-terminal targeting sequence, it activates L-aspartate with ATP and esterifies it to mitochondrial tRNA(Asp), supplying Asp-tRNA(Asp) for synthesis of the 13 mitochondrially encoded respiratory-chain proteins. Its structure closely resembles E. coli AspRS but has an enlarged catalytic groove and adaptations to the structurally degenerate mitochondrial tRNA. The enzyme is soluble in the matrix, with an additional pool peripherally associated with mitochondrial membranes. DARS2 protein levels are regulated by acetylation and SCF-FBXO24-mediated ubiquitination, and release of DARS2 from stimulated cells with effects on macrophage cytokine production has been reported. Biallelic variants that reduce aminoacylation cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) and axonal Charcot-Marie-Tooth disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000049 tRNA binding | TAS PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | ACCEPT | Summary: DARS2 binds the tRNA substrate used in its aminoacylation reaction. Reason: The 2005 abstract explicitly reports aminoacylation of bacterial and human mitochondrial tRNAs. The full 2005 original remains unavailable, so the TAS annotation is retained with curator deference. Independent human mtAspRS binding experiments in PMID:23275545 directly measure association with mitochondrial and E. coli tRNA(Asp); they do not establish binding to every tRNA species. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: Nucleotide binding is true but subsumed by the retained ATP-binding annotations. Reason: The literal InterPro sources match the target and the class II aminoacyl-tRNA synthetase domain maps to nucleotide binding. DARS2 uses ATP in amino-acid activation. Current is_a/part_of ancestry places the accepted GO:0005524 ATP binding below this term; the broad source remains positive rather than being treated as a failed mapping. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000002 |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: Nucleic-acid binding is represented more informatively by the retained tRNA-binding annotation. Reason: IPR004365 is the matching OB-fold nucleic-acid-binding domain. Its generic mapping does not distinguish DNA from the actual tRNA substrate. The accepted GO:0000049 tRNA binding is a verified descendant and is independently supported by the 2013 human enzyme–tRNA binding assays. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000002 |
| GO:0004812 aminoacyl-tRNA ligase activity | IEA GO_REF:0000120 | TOO GENERAL | Summary: The broad aminoacyl-tRNA ligase claim is already entailed by accepted aspartate-tRNA ligase activity. Reason: All three literal InterPro sources are present on human DARS2, including the class II catalytic domain. The retrieved current ARBA00026908 has 30 alternative branches, none of which completely matches the current target predicates; that current-rule boundary does not erase the preserved historical source assertion or the positive domain evidence. Human experiments establish the already accepted GO:0004815, a strict descendant of this term. No current ARBA match or failure of catalysis is invented. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000120 |
| GO:0004815 aspartate-tRNA ligase activity | EXP PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | ACCEPT | Summary: The original biochemical characterization supports human mitochondrial aspartate-tRNA ligase activity. Reason: PMID:15779907 explicitly characterizes human mitochondrial AspRS and reports aminoacylation of E. coli and human mitochondrial tRNAs. The full original could not be recovered, so its exact constructs and substrate panel remain unverified. The positive specific activity is independently reproduced with human mtAspRS in the 2007 and 2013 original assays; this retention does not resolve the separate tRNA(Asn) assertion. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0004815 aspartate-tRNA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The exact PAINT ancestry supports the conserved aspartate-tRNA ligase function. Reason: The actual PTHR22594 tree places human DARS2 PTN002503203 below PTN000502597. The literal GO:0004815 IBD uses SGD:S000006025, UniProtKB:P21889 and UniProtKB:Q6PI48. The yeast donor resolves to mitochondrial MSD1/P15179 and the bacterial donor to E. coli aspS; current records contain experimental activity evidence. Human self evidence is legitimate descendant grounding, not circularity. No target-specific loss of this demonstrated activity is indicated. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000502597 SUPPORTS TRANSFER The literal on-path IBD is supported by experimental MSD1, aspS and human DARS2 descendant annotations; self evidence is legitimate. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000033 |
| GO:0004815 aspartate-tRNA ligase activity | IDA PMID:23275545 Thermodynamic properties distinguish human mitochondrial asp... | ACCEPT | Summary: The 2013 study directly assays human mitochondrial aspartate-tRNA ligase activity. Reason: Recombinant human HsaDRS2 begins at I41 and was expressed in E. coli. Table 1 and Methods measure charging of human mitochondrial and E. coli tRNA(Asp) transcripts with aspartate; the human enzyme acts on both. The 40-residue experimental truncation must not be presented as proof of the predicted native 48–645 maturation boundary. Cross-species Asp recognition is not evidence of tRNA(Asn) charging. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0004815 aspartate-tRNA ligase activity | IDA PMID:40814755 Biallelic Variants in the DARS2 Gene as a Novel Cause of Axo... | ACCEPT | Summary: Wild-type human DARS2 is an active positive control in the 2025 aminoacylation experiment. Reason: The study transfects HEK293 cells with wild-type pCMV6-DARS2 or p.Pro503Leu, with mock and untransfected controls. Lysates are incubated with ATP, E. coli total tRNA and isotope-labeled aspartate; mock activity is subtracted. The mutant retains about 25% of the wild-type signal. This supports DARS2-dependent aspartate-tRNA ligase activity, without pretending this lysate experiment is a purified mitochondrial-tRNA specificity assay. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. PMID:40814755 We observed that DARS2 p.Pro503Leu showed only 25% residual aminoacylation activity, showing a significant reduction compared to wild‐type DARS2. |
| GO:0004815 aspartate-tRNA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The enzyme and reaction mappings agree with the directly demonstrated Asp-tRNA(Asp) reaction. Reason: The literal EC:6.1.1.12 and RHEA:19649 annotation describes ATP-dependent esterification of tRNA(Asp) with L-aspartate. The official human catalytic reaction and independent human enzyme assays agree. This source is not the separate non-discriminating EC:6.1.1.23 activity. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000120 |
| GO:0005515 protein binding | IPI PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | UNDECIDED | Summary: The precise DARS2–YARS2 interaction remains unverified. Reason: The original source is a biochemical characterization of human mitochondrial AspRS and TyrRS, not a generic high-throughput screen. Its complete abstract establishes each enzyme but does not state a heteromeric interaction, and bounded original-access attempts failed. Current literal interaction queries contain no matching pair for this PMID; absence from that service is not disproof of the historical IPI annotation. The title naming both enzymes cannot itself establish their binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex AP-MS co-purification with testis-specific cytosolic GAPDHS; generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. GAPDHS is a sperm-specific cytosolic glycolytic enzyme and DARS2 is a mitochondrial matrix enzyme, so the HEK293T/HCT116 co-purification does not point to a physiological complex. Recasting the row as enzyme binding would describe the partner, not a DARS2 activity. This supersedes the earlier MODIFY to GO:0019899. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: The HSPD1 association supports protein-folding chaperone binding. Reason: The exact positive BioPlex 2.0 record has HSPD1/P10809 as the tagged bait and DARS2 as prey, with spoke expansion. Official HSPD1 is the mitochondrial Hsp60 chaperonin. GO:0051087 describes binding to a protein-folding chaperone and does not require DARS2 itself to be a chaperone. The assay establishes contextual co-purification, not purified binary binding or a DARS2 co-chaperone function. Re-review 2026-10-20: retained because HSPD1 (Hsp60) is itself a mitochondrial matrix chaperonin, so the partner shares the DARS2 compartment, and the pair recurs in independent AP-MS and crosslinking datasets. This is a binding-partner annotation, not a core DARS2 activity. Proposed replacements: protein-folding chaperone binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive... | REMOVE | Summary: BioID proximity labeling by HSPD1 bait; proximity is not binding and generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. MAC-tag BioID labels neighbouring proteins and does not by itself show physical association. The HSPD1 association is represented by the AP-MS (PMID:28514442, PMID:33961781) and crosslinking (PMID:30021884) rows, which are refined to protein-folding chaperone binding. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | MODIFY | Summary: The positive HSPD1 crosslink supports the chaperone-binding class. Reason: The literal record is a positive physical association between Q6PI48 and P10809 detected by crosslinking. The cached source contains its abstract and Discussion, including intact-nucleus preparation and limits on orthogonal validation, but not the complete target peptide table. Curator deference and the exact experimental pair support refinement to the established HSPD1 chaperone class, independently corroborated by co-purification. Do not infer a nuclear DARS2 function or measured folding assistance from this pair. Re-review 2026-10-20: retained because HSPD1 (Hsp60) is itself a mitochondrial matrix chaperonin, so the partner shares the DARS2 compartment, and the pair recurs in independent AP-MS and crosslinking datasets. This is a binding-partner annotation, not a core DARS2 activity. Proposed replacements: protein-folding chaperone binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with CDIPT (ER-membrane phosphatidylinositol synthase); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with CDIPT (ER-membrane phosphatidylinositol synthase) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with CYB561 (secretory-vesicle membrane cytochrome b561); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with CYB561 (secretory-vesicle membrane cytochrome b561) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with ALDH18A1/P5CS (mitochondrial pyrroline-5-carboxylate synthase); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with ALDH18A1/P5CS (mitochondrial pyrroline-5-carboxylate synthase) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with PLP2 (MARVEL-domain membrane protein); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with PLP2 (MARVEL-domain membrane protein) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with AOC3 (cell-surface amine oxidase); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with AOC3 (cell-surface amine oxidase) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with a COL8A2 (type VIII collagen) construct; generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with a COL8A2 (type VIII collagen) construct comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with UNC50 (Golgi membrane protein); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with UNC50 (Golgi membrane protein) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with TSPAN33 (tetraspanin); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with TSPAN33 (tetraspanin) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with TMEM239 isoform 2; generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with TMEM239 isoform 2 comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with THSD7B (type I membrane thrombospondin-repeat protein); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with THSD7B (type I membrane thrombospondin-repeat protein) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary two-hybrid hit with FETUB (secreted fetuin-B); generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The pair with FETUB (secreted fetuin-B) comes from the proteome-scale HuRI GAL4 two-hybrid screen, which tests fusion proteins in yeast nuclei, outside the native mitochondrial matrix environment of DARS2. No follow-up study links this partner to DARS2 activity, and refining the row to a partner-class term (enzyme, collagen or transporter binding) would describe the partner rather than a function DARS2 performs. This supersedes the earlier partner-class MODIFY/KEEP_AS_NON_CORE decisions on this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex AP-MS co-purification with testis-specific cytosolic GAPDHS; generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. GAPDHS is a sperm-specific cytosolic glycolytic enzyme and DARS2 is a mitochondrial matrix enzyme, so the HEK293T/HCT116 co-purification does not point to a physiological complex. Recasting the row as enzyme binding would describe the partner, not a DARS2 activity. This supersedes the earlier MODIFY to GO:0019899. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Two positive BioPlex 3.0 records support the HSPD1 chaperone-binding class. Reason: Both literal records use tagged human HSPD1/P10809 as bait and DARS2 as prey in AP-MS associations with spoke expansion. The returned source text is partial despite its full-text flag; exact pairs and official chaperonin identity, corroborated by the earlier BioPlex and crosslink sources, support GO:0051087. These are contextual associations and do not show that DARS2 catalyzes protein folding. Re-review 2026-10-20: retained because HSPD1 (Hsp60) is itself a mitochondrial matrix chaperonin, so the partner shares the DARS2 compartment, and the pair recurs in independent AP-MS and crosslinking datasets. This is a binding-partner annotation, not a core DARS2 activity. Proposed replacements: protein-folding chaperone binding |
| GO:0005515 protein binding | IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy... | REMOVE | Summary: MaMTH screen hit with F508del-CFTR; generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The interaction was detected in a pooled split-ubiquitin MaMTH screen with misfolded F508del-CFTR, an ER-retained plasma-membrane channel. DARS2 is a mitochondrial matrix enzyme; no study shows DARS2 acting on CFTR. Refining to transmembrane transporter binding would describe the partner rather than a DARS2 function. This supersedes the earlier MODIFY to GO:0044325. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | REMOVE | Summary: APEX2/TurboID proximity labeling around mutant CFTR; generic binding is uninformative. Reason: Bare protein binding is uninformative about DARS2 function and is removed under the repository protein-binding policy; removal does not assert that the reported interaction is false. The records come from proximity labeling around CFTR G551D and W1282X constructs, which labels proteins within roughly 10-20 nm under denaturing capture and does not establish binding. No DARS2 function in CFTR biology is supported. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is an integral substrate-recognition feature of the active ligase. Reason: The literal InterPro sources match the target and their current mappings include ATP binding. Human enzyme assays require ATP to activate aspartate, and the 2013 study measures binding of an aspartyl-adenylate analogue. This supports the source annotation without turning substrate binding into an additional independent core activity. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000002 |
| GO:0005524 ATP binding | TAS PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | ACCEPT | Summary: The biochemical characterization supports ATP binding as part of amino-acid activation. Reason: The 2005 paper identifies active human mitochondrial AspRS; its full original remains unavailable. The accepted ATP-binding claim agrees with the enzyme chemistry and independent 2013 Methods and adenylate-analogue binding experiments. It does not imply a separate ATPase role. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | TOO GENERAL | Summary: Cytoplasm is a broad true compartment already entailed by the mitochondrial annotations. Reason: Current ARBA00026971 branch 252 matches IPR002312, IPR004115 and IPR004364 on DARS2; the literal IPR004115 source is a GAD-like structural domain, not proof of cytosolic activity. GO:0005737 includes subcellular organelles, and accepted mitochondrion is a verified descendant. The broad mapping is not contradicted by mitochondrial targeting and does not mean cytosol. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000120 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: MitoCoP contains direct experimental evidence for mitochondrial DARS2. Reason: Original Table S1 sheet A row 291 contains Q6PI48/DARS2, protein group 7262: class 1 subtractive proteomics, cluster 1 spatial profiling and class 1 importomics, with pool 1–3 evidence; sheet B row 264 includes the gene. The same row classifies its membrane association as Peripheral. This is not a literature-only pool-4 inference. The broad organelle annotation remains useful and does not by itself resolve matrix versus intermembrane space. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrial IBA follows the actual DARS2 ancestry and experimental donors. Reason: Human PTN002503203 descends from PTN000502598 in the actual PTHR22594 tree. Its literal mitochondrial IBD has SGD:S000006025 and UniProtKB:Q6PI48; yeast MSD1/P15179 has experimental mitochondrial records, and the human source is legitimate descendant evidence. No donor-count or self-evidence objection applies. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000502598 SUPPORTS TRANSFER The literal on-path mitochondrial IBD uses experimental yeast MSD1 and human DARS2 evidence. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000033 |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: The Human Protein Atlas supports mitochondrial localization. Reason: The current official ENSG00000117593/DARS2 record lists mitochondria as its main subcellular location, supported immunofluorescence and antibodies HPA026506/HPA026528. It also lists nucleoplasm as an additional location; that context does not negate the mitochondrial annotation or establish a new nuclear function. No product-specific antibody recognition or matrix-resolution claim is made. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000052 |
| GO:0005739 mitochondrion | TAS PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | ACCEPT | Summary: The mitochondrial assignment is supported by the original characterization and independent experiments. Reason: The 2005 abstract explicitly identifies the human mitochondrial synthetase and mitochondrial-tRNA charging. Full original access is unavailable, so the TAS evidence is retained with curator deference. Human-cell fractionation, imaging and MitoCoP independently corroborate the organelle location. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0005759 mitochondrial matrix | EXP PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | ACCEPT | Summary: Retain the curated matrix location while distinguishing source access from independent organelle evidence. Reason: The original 2005 full text is unavailable, so its specific matrix-localization experiment cannot be reconstructed. The location is consistent with mitochondrial tRNA charging and is independently represented in the reviewed UniProt and literal Reactome catalyst model. The 2018 soluble fraction contains matrix and intermembrane-space material and is not itself a resolved matrix assay. Retention is curator-deferential, not a new topology experiment. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. Reactome:R-HSA-380229 |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt matrix vocabulary mapping is consistent with the established catalytic compartment. Reason: The literal SL-0170 source maps mitochondrial matrix to GO:0005759. The official record and the Reactome DARS2 catalyst agree. Matrix assignment is kept distinct from the less resolved soluble-fraction experiment and from peripheral membrane association; neither establishes a membrane face or the exact site of flux. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000044 Reactome:R-HSA-380229 |
| GO:0005759 mitochondrial matrix | IMP PMID:30006346 Three human aminoacyl-tRNA synthetases have distinct sub-mit... | ACCEPT | Summary: The source supports a soluble mitochondrial DARS2 pool, with matrix retained from the integrated evidence. Reason: PMID:30006346 detects endogenous DARS2 in both soluble and membrane fractions and compares wild-type and disease variants. Its sonication/ultracentrifugation protocol explicitly combines matrix with intermembrane-space material in the soluble fraction; it cannot independently assign a membrane side or resolve these soluble compartments. Retain the curated gene-level matrix claim with the original biochemical/UniProt/Reactome context, not as a claim that this experiment alone resolved the matrix. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. Reactome:R-HSA-380229 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-380229 | ACCEPT | Summary: The literal Reactome catalyst is located in mitochondrial matrix. Reason: Reaction R-HSA-380229 uses catalyst activity 379660, DARS2 dimer 379573 and protein entity 379679, which resolves to human Q6PI48 with modeled coordinates 48–645 and matrix compartment 5460. The reaction forms Asp-tRNA(Asp) from aspartate, tRNA(Asp) and ATP. Coordinates reflect the model/UniProt maturation annotation, not a newly measured cleavage site. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. Reactome:R-HSA-380229 |
| GO:0006418 tRNA aminoacylation for protein translation | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad translation-linked charging process is represented by the more specific mitochondrial process. Reason: The matching class II synthetase domains support tRNA aminoacylation. GO:0070127, proposed from the directly inspected human mitochondrial-tRNA assay on row 53, is an is_a/part_of descendant of GO:0006418. The electronic source remains positive; the action avoids duplicate broad process coverage rather than questioning catalytic participation. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000002 |
| GO:0006422 obsolete aspartyl-tRNA aminoacylation | IBA GO_REF:0000033 | MODIFY | Summary: Retain the inherited Asp-charging biology using the current mitochondrial aminoacylation process term. Reason: The actual PTN000502597 IBD for GO:0006422 is on the DARS2 path and uses yeast MSD1 and E. coli aspS evidence; current bacterial records retain experimental Asp-charging annotations. The PAINT placement is sound. GO:0006422 is now obsolete because it restates the molecular function; the target performs mitochondrial tRNA aminoacylation, directly supported by human mitochondrial tRNA(Asp) assays. Preserve the original obsolete ID and replace the reviewed process with GO:0070127, without alleging donor invalidity. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000502597 SUPPORTS TRANSFER The source IBD and Asp-charging biology are valid. The original process ID is now obsolete; human mitochondrial charging supports the proposed current process term. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000033 |
| GO:0016874 ligase activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: Ligase activity is true but already entailed by accepted aspartate-tRNA ligase activity. Reason: IPR004524 matches human DARS2 and describes the type 1 bacterial/mitochondrial aspartate-tRNA ligase family. Its broad GO:0016874 mapping is biologically correct. The accepted GO:0004815 is a verified strict descendant and supplies the substrate-specific function; no loss of enzymatic activity is proposed. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. GO_REF:0000002 |
| GO:0031966 mitochondrial membrane | IDA PMID:40814755 Biallelic Variants in the DARS2 Gene as a Novel Cause of Axo... | KEEP AS NON CORE | Summary: Retain mitochondrial membrane association with the imaging and fractionation evidence distinguished. Reason: PMID:40814755 images DARS2 and TOMM20 in control and patient fibroblasts; that confocal colocalization resolves the mitochondrial network, not membrane insertion or topology. Independent PMID:30006346 directly demonstrates an electrostatically associated peripheral membrane pool, also corroborated by the MitoCoP Peripheral category. The integrated gene-level membrane claim is supported, without presenting the 2025 image as a resolved membrane assay or assigning charging flux to that pool. Re-review 2026-10-20: changed from ACCEPT to KEEP_AS_NON_CORE. The peripheral membrane pool is experimentally supported, but the defining activity, charging of mitochondrial tRNA(Asp) for mitoribosome translation, is placed in the matrix (core location). Membrane association is a real but secondary localization whose functional significance is unknown. Supporting Evidence: PMID:30006346 mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The UniProt mitochondrial membrane mapping agrees with peripheral association. Reason: The literal SL-0171 mapping corresponds to mitochondrial membrane. The direct fractionation and chemical-extraction experiments in PMID:30006346 support peripheral association, including release by salt and alkaline carbonate. This does not mean DARS2 is an integral membrane protein or establish inner versus outer membrane or either membrane face. Re-review 2026-10-20: changed from ACCEPT to KEEP_AS_NON_CORE. The peripheral membrane pool is experimentally supported, but the defining activity, charging of mitochondrial tRNA(Asp) for mitoribosome translation, is placed in the matrix (core location). Membrane association is a real but secondary localization whose functional significance is unknown. Supporting Evidence: PMID:30006346 mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions GO_REF:0000044 |
| GO:0031966 mitochondrial membrane | IMP PMID:30006346 Three human aminoacyl-tRNA synthetases have distinct sub-mit... | KEEP AS NON CORE | Summary: The 2018 experiments directly establish a peripheral mitochondrial membrane pool. Reason: Endogenous DARS2 in HEK293T mitochondria partitions between soluble and membrane fractions. Tagged human wild-type and variant proteins are also analyzed in BHK21 cells. Membrane association is disrupted by high salt, carbonate and urea, consistent with electrostatic peripheral association. The study does not separate inner from outer membrane or show that the membrane pool catalyzes mitochondrial tRNA charging. Re-review 2026-10-20: changed from ACCEPT to KEEP_AS_NON_CORE. The peripheral membrane pool is experimentally supported, but the defining activity, charging of mitochondrial tRNA(Asp) for mitoribosome translation, is placed in the matrix (core location). Membrane association is a real but secondary localization whose functional significance is unknown. Supporting Evidence: PMID:30006346 mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions |
| GO:0042803 protein homodimerization activity | IPI PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | ACCEPT | Summary: The original biochemical source explicitly describes a dimeric enzyme. Reason: The complete 2005 abstract reports dimeric organization of human mitochondrial AspRS. Full original access remains unavailable, but the independent 2013 structural analysis directly observes the homodimer. The absence of a current literal self-pair in the queried interaction service is not evidence against this well-supported assembly. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. PMID:23275545 The crystal structure of the homodimeric bacterial-type human mitochondrial aspartyl-tRNA synthetase (DRS) confirmed a 3D architecture close to that of Escherichia coli DRS. |
| GO:0042803 protein homodimerization activity | IPI PMID:23275545 Thermodynamic properties distinguish human mitochondrial asp... | ACCEPT | Summary: The 2013 structure and solution characterization support homodimerization. Reason: Human mtAspRS with an experimental deletion of residues 1–40 was purified as a dimer and crystallized; the asymmetric unit contains two dimers. The resolved protein coordinates span residues 42–630, with terminal residues including the affinity tag disordered. This supports homodimerization without claiming a full 645-residue precursor structure or experimentally mapped native processing. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. PMID:23275545 The crystal structure of the homodimeric bacterial-type human mitochondrial aspartyl-tRNA synthetase (DRS) confirmed a 3D architecture close to that of Escherichia coli DRS. |
| GO:0043039 tRNA charging | IDA PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | TOO GENERAL | Summary: The positive tRNA-charging result is represented by the mitochondrial aminoacylation process. Reason: The 2005 abstract supports aminoacylation of human mitochondrial tRNAs; full source access remains unavailable. The current GO:0070127 mitochondrial process proposed from the independent inspected 2013 assay is a verified descendant of GO:0043039. The original positive experiment remains in the review; the broad term is not treated as false. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0043039 tRNA charging | IDA PMID:17384640 Mitochondrial aspartyl-tRNA synthetase deficiency causes leu... | TOO GENERAL | Summary: The positive charging assay is covered by the more specific mitochondrial aminoacylation process. Reason: The recovered 2007 Results and Methods test purified wild-type human mtAspRS and variants on T7 transcripts of E. coli tRNA(Asp). This establishes the charging step but does not by itself test human mitochondrial tRNA. Independent PMID:23275545 does so and supports the already proposed GO:0070127 descendant. The broad positive source remains valid and is not removed. Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0050560 aspartate-tRNA(Asn) ligase activity | IDA PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | MODIFY | Summary: The 2005 characterization supports cognate aspartate-tRNA(Asp) ligase activity; the non-discriminating tRNA(Asx) term is not supported. Reason: GO:0050560 describes non-discriminating Asp-tRNA(Asx) activity (EC:6.1.1.23), whose biological role is to supply Asp-tRNA(Asn) for an amidotransferase in organisms lacking asparaginyl-tRNA synthetase. The 2005 abstract reports an aspartyl-tRNA synthetase that charges E. coli and human mitochondrial tRNAs, and human mitochondria have a dedicated asparaginyl-tRNA synthetase (NARS2, Q96I59, PANTHER PTHR22594:SF34). UniProt curators, who read this paper, record only EC:6.1.1.12 (tRNA(Asp)) with ECO:0000269 citing it. Phylogenetically, DARS2 is in PTHR22594:SF5 with the discriminating E. coli AspS (P21889) and yeast MSD1, the clade at which PAINT placed GO:0004815; no GO:0050560 IBD exists on this path. Re-review 2026-10-20 therefore changes the earlier UNDECIDED to MODIFY to the cognate activity, consistent with the PMID:17384640 row. The full 2005 text was not read; if it contains a direct tRNA(Asn) charging assay this should be revisited. Proposed replacements: aspartate-tRNA ligase activity Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0050560 aspartate-tRNA(Asn) ligase activity | IDA PMID:17384640 Mitochondrial aspartyl-tRNA synthetase deficiency causes leu... | MODIFY | Summary: The recovered 2007 experiment supports aspartate-tRNA(Asp) ligase activity. Reason: The original Results introduce purified wild-type human mtAspRS and five variants assayed on tRNA(Asp); Methods explicitly specify T7 transcripts of E. coli tRNA(Asp). This demonstrates GO:0004815. GO:0050560 instead describes non-discriminating Asp-tRNA(Asx) activity. Refine to the tested substrate while preserving the original source fields; the result is not a negative experiment on tRNA(Asn). Proposed replacements: aspartate-tRNA ligase activity Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0070145 obsolete mitochondrial asparaginyl-tRNA aminoacylation | IC PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | MODIFY | Summary: The IC inference rests on the GO:0050560 row, which is refined to cognate Asp charging; the supported process is mitochondrial tRNA aminoacylation. Reason: This IC row was inferred from GO:0050560 on PMID:15779907. That premise is refined in this review to GO:0004815 aspartate-tRNA(Asp) ligase activity (see the GO:0050560 rows), and human mitochondria charge tRNA(Asn) with the dedicated NARS2. GO:0070145 is obsolete. The process DARS2 performs is charging of mitochondrial tRNA(Asp) for mitochondrial translation, so the row is refined to GO:0070127, consistent with the PMID:23275545 row on the same obsolete term. Re-review 2026-10-20 replaces the earlier UNDECIDED. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
| GO:0070145 obsolete mitochondrial asparaginyl-tRNA aminoacylation | IDA PMID:23275545 Thermodynamic properties distinguish human mitochondrial asp... | MODIFY | Summary: The original 2013 experiment supports mitochondrial tRNA aminoacylation, not an asparaginyl-specific process. Reason: The inspected Methods, Results and Table 1 use recombinant human mtAspRS beginning at I41 and either human mitochondrial or E. coli tRNA(Asp) transcripts. The non-cognate comparison is cross-species tRNA(Asp), not tRNA(Asn), and the amino acid is aspartate. Preserve the original obsolete GO:0070145 source ID while proposing the current GO:0070127 process actually supported by human mitochondrial-tRNA charging. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:15779907 Both belong to the expected class of synthetases, have a dimeric organization, and aminoacylate Escherichia coli tRNAs as well as in vitro transcribed human mitochondrial tRNAs. |
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Download this section (compressed HTML)Q: Which endogenous mature DARS2 species occupy the soluble and peripheral mitochondrial membrane pools, and where does tRNA(Asp) charging occur?
Q: Is human DARS2 strictly discriminating against mitochondrial tRNA(Asn) in vitro, as predicted by its SF5 placement with E. coli AspS, and what assay underlies its reported interaction with YARS2?
Q: Does extracellular DARS2 act without a delivery reagent, through a defined receptor or uptake route, and is its aminoacylation activity required?
Experiment: Compare purified human DARS2 charging of sequence-verified mitochondrial tRNA(Asp) and tRNA(Asn), with both substrate integrity controls and direct identification of the aminoacylated products. Keep the experimental truncation and affinity tags explicit.
Experiment: Combine endogenous N-terminal peptide mapping with submitochondrial fractionation and fraction-specific aminoacylation assays to distinguish mature species, peripheral attachment and the location of charging activity.
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