SLC25A12 (Aralar / AGC1) is a calcium-regulated mitochondrial aspartate-glutamate carrier of the SLC25 mitochondrial carrier family. It is an electrogenic antiporter of the inner mitochondrial membrane that exports L-aspartate from the matrix in exchange for cytosolic L-glutamate plus a proton. This antiport is the key, effectively irreversible step of the malate-aspartate shuttle, which transfers reducing equivalents (cytosolic NADH) into mitochondria for oxidation; the carrier also supplies mitochondrially derived aspartate to the cytosol. The protein has a unique three-domain architecture: an N-terminal regulatory domain bearing EF-hand motifs that binds Ca2+ in the intermembrane space and gates transport, a six-transmembrane-helix mitochondrial carrier domain, and a short C-terminal domain; it functions as a homodimer. In addition to aspartate/glutamate it can exchange L-cysteinesulfinate (3-sulfino-L-alanine) for glutamate or aspartate, but it does not transport GABA or L-glutamine. Aralar is expressed predominantly in excitable tissues (heart, skeletal muscle) and neurons; in neurons its aspartate efflux is required for N-acetylaspartate production and myelination. Biallelic loss-of-function mutations cause developmental and epileptic encephalopathy with global cerebral hypomyelination.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005313 L-glutamate transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the glutamate side of the antiport. This is correct but less specific than the aspartate:glutamate antiporter activity that is directly supported experimentally. Aralar imports glutamate with a proton in exchange for aspartate. Reason: Consistent with experimental transport data; glutamate transmembrane transporter activity is a genuine parent of the specific antiporter function (GO:0000515). Supporting Evidence: PMID:25410934 import glutamate together with a proton into the mitochondrial matrix and export aspartate |
| GO:0015183 L-aspartate transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the aspartate side of the antiport. Correct and well supported experimentally, though the specific aspartate:glutamate antiporter term (GO:0000515) better captures the coupled exchange. Reason: L-aspartate transmembrane transporter activity is a direct parent of the experimentally demonstrated antiporter activity and is fully consistent with the data. Supporting Evidence: PMID:25410934 import glutamate together with a proton into the mitochondrial matrix and export aspartate |
| GO:0043490 malate-aspartate shuttle | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the malate-aspartate shuttle, the central process the carrier serves. This is a core biological process for SLC25A12 and is also supported experimentally. Reason: Aralar makes the malate-aspartate NADH shuttle directional; overexpression raises shuttle activity in human cells. Supporting Evidence: PMID:11566871 increased the activity of the malate/aspartate NADH shuttle |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) localization to the mitochondrial inner membrane, where the carrier operates. Consistent with multiple experimental localization annotations. Reason: Correct core location; the carrier domain is a multi-pass inner-membrane protein. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0015810 aspartate transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation for the aspartate-transport process, a component of the aspartate/glutamate antiport. Also directly supported experimentally. Reason: Aspartate transmembrane transport is part of the demonstrated antiport activity. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt that favors efflux of aspartate and entry of glutamate and proton |
| GO:0015813 L-glutamate transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation for the glutamate-transport process, the other half of the antiport. Also directly supported experimentally. Reason: L-glutamate transmembrane transport is part of the demonstrated antiport activity. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt that favors efflux of aspartate and entry of glutamate and proton |
| GO:0000514 3-sulfino-L-alanine: proton, glutamate antiporter activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic prediction of cysteinesulfinate (3-sulfino-L-alanine)/glutamate antiporter activity. This is a genuine secondary activity of the carrier that is also independently supported by an experimental (IDA) annotation from PMID:11566871. Reason: The carrier transports L-cysteinesulfinate in exchange for glutamate; the IEA is redundant with the experimental IDA annotation of the same term. Supporting Evidence: PMID:11566871 AGC also transports cysteinesulfinate in exchange for either aspartate or glutamate |
| GO:0000515 aspartate:glutamate, proton antiporter activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic prediction of the core aspartate:glutamate proton antiporter activity. This is the primary molecular function of SLC25A12 and is redundant with the experimental (IDA/EXP) annotations of the same term. Reason: Core function; corroborated by multiple experimental annotations to GO:0000515. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt that favors efflux of aspartate and entry of glutamate and proton |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/ARBA) annotation of calcium ion binding via the EF-hand motifs of the regulatory N-terminal domain. This is a real secondary molecular function and is redundant with experimental (IDA) calcium-binding annotations. Reason: EF-hand-mediated Ca2+ binding is experimentally established and regulates transport. Supporting Evidence: PMID:25410934 Only EF-hand 2 binds calcium |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (UniProt Subcellular Location) annotation to the mitochondrial inner membrane, redundant with multiple experimental localization annotations. Reason: Correct core location, corroborated by IDA/EXP annotations. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0015804 neutral amino acid transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: GOC inter-ontology inference from the 3-sulfino-L-alanine antiporter term. The physiological substrates of aralar (aspartate, glutamate) are acidic amino acids; cysteinesulfinate is an acidic sulfinic amino acid analogue. Labeling this a "neutral amino acid transport" function mischaracterizes the carrier's substrate class and is at best a minor over-annotation. Reason: The carrier's substrates are acidic/dicarboxylic amino acids, not neutral amino acids; this auto-generated term does not reflect the demonstrated selectivity. |
| GO:0043490 malate-aspartate shuttle | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to the malate-aspartate shuttle, redundant with the experimental (IDA/IGI) annotations of this core process. Reason: Core process; corroborated experimentally. Supporting Evidence: PMID:11566871 increased the activity of the malate/aspartate NADH shuttle |
| GO:0051592 response to calcium ion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation for response to calcium ion, reflecting Ca2+ regulation of transport activity. Redundant with the experimental IDA annotation of this term. Reason: Transport activity is stimulated by Ca2+ binding to the regulatory domain in the intermembrane space; a genuine (non-core) regulatory response. Supporting Evidence: PMID:11566871 was stimulated by Ca 2+ on the external side of |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation to the generic transmembrane transport process. Correct but very general; the specific aspartate/glutamate transport processes are already annotated with experimental evidence. Reason: Accurate but non-informative parent of the specific transport processes; retained as non-core rather than removed. |
| GO:0070778 L-aspartate transmembrane transport | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (combined-IEA) annotation to L-aspartate transmembrane transport, inferred from the aspartate transporter/antiporter MF terms. Correct and essentially equivalent to the experimentally supported aspartate-transport process. Reason: Reflects the demonstrated aspartate-transport half of the antiport. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt that favors efflux of aspartate and entry of glutamate and proton |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: GOC inter-ontology inference (from the antiporter MF terms) that the carrier is involved in proton transmembrane transport. A proton is co-transported with glutamate as an obligatory part of the electrogenic antiport, so this is not a standalone proton-transport function; it over-states the carrier's role. Reason: The proton flux is a coupled component of aspartate/glutamate antiport, not an independent proton-transport activity; the auto-generated term is misleading. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IntAct/BioPlex affinity-capture interaction with citrin (SLC25A13; Q9UJS0), the paralogous aspartate/glutamate carrier. "protein binding" is an uninformative molecular function term. The homodimeric/self-association biology is better captured by GO:0042802 (identical protein binding). Reason: Bare "protein binding" carries no functional information; kept per policy (not removed) but flagged as over-annotated. |
| GO:0005515 protein binding | IPI PMID:31767682 The microRNAs miR-302b and miR-372 regulate mitochondrial me... | MARK AS OVER ANNOTATED | Summary: IntAct interaction with MAVS (Q7Z434). This reflects a context-specific role in which SLC25A12, as part of a prohibitin complex, associates with the mitochondrial antiviral-signaling protein, linking mitochondrial metabolism to antiviral innate immunity. As a molecular-function term, bare "protein binding" is uninformative. Reason: Uninformative bare MF; the interaction itself is real but is a regulatory/context finding, not a core molecular function. Supporting Evidence: PMID:31767682 associates with the mitochondrial antiviral-signaling |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IntAct/BioPlex-type interaction with citrin (SLC25A13; Q9UJS0). As with the other "protein binding" IPIs, this is an uninformative molecular-function term. Reason: Bare "protein binding" carries no functional information; kept per policy. |
| GO:0005515 protein binding | IPI PMID:40355756 The solute carrier superfamily interactome. | MARK AS OVER ANNOTATED | Summary: Interaction with citrin (SLC25A13; Q9UJS0) reported in an SLC-superfamily interactome screen. Uninformative bare molecular-function term. Reason: Bare "protein binding" carries no functional information; kept per policy. |
| GO:0000515 aspartate:glutamate, proton antiporter activity | EXP PMID:19641205 AGC1 deficiency associated with global cerebral hypomyelinat... | ACCEPT | Summary: Experimental (EXP) annotation of the core aspartate:glutamate proton antiporter activity. Functional analysis of a disease mutant (Q590R) showed abolished transport activity, confirming that this is the essential function of the protein. Reason: Directly demonstrated core molecular function. Supporting Evidence: PMID:19641205 showed abolished activity |
| GO:0000515 aspartate:glutamate, proton antiporter activity | EXP PMID:38945283 The mitochondrial aspartate/glutamate carrier does not trans... | ACCEPT | Summary: Experimental (EXP) annotation of the aspartate:glutamate proton antiporter activity. This study reconfirmed the canonical aspartate/glutamate exchange while demonstrating that the carrier does not transport GABA. Reason: Directly demonstrated core molecular function. Supporting Evidence: PMID:38945283 AGC does not transport GABA |
| GO:0005743 mitochondrial inner membrane | EXP PMID:19641205 AGC1 deficiency associated with global cerebral hypomyelinat... | ACCEPT | Summary: Experimental localization to the mitochondrial inner membrane; the disease mutant was correctly targeted to the inner membrane (localization unaffected). Core location. Reason: Experimentally supported core location. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | EXP PMID:24515575 AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelinat... | ACCEPT | Summary: Experimental localization to the mitochondrial inner membrane; the R353Q disease mutant retained normal inner-membrane localization. Core location. Reason: Experimentally supported core location. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | EXP PMID:9722566 Molecular cloning of Aralar, a new member of the mitochondri... | ACCEPT | Summary: Experimental localization to the mitochondrial inner membrane from the original cloning/characterization of aralar. Core location. Reason: Experimentally supported core location. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0043490 malate-aspartate shuttle | IGI PMID:37647199 The malate-aspartate shuttle is important for de novo serine... | ACCEPT | Summary: Genetic-interaction (IGI) evidence that SLC25A12 is a component of the malate-aspartate shuttle, from a study that genetically disrupted each shuttle component in HEK293 cells and traced the metabolic consequences. Core process. Reason: Supports the carrier's role as a component of the malate-aspartate shuttle. Supporting Evidence: PMID:37647199 genetically disrupted each MAS component |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput proteomic localization to mitochondrion. Correct but less specific than the experimentally supported inner-membrane localization. Reason: Accurate but a general parent of the mitochondrial inner membrane location. |
| GO:0000514 3-sulfino-L-alanine: proton, glutamate antiporter activity | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct assay (IDA) demonstrating cysteinesulfinate (3-sulfino-L-alanine) exchange for glutamate in reconstituted proteoliposomes. A genuine secondary transport activity of the carrier. Reason: Experimentally demonstrated secondary (non-core) transport activity. Supporting Evidence: PMID:11566871 AGC also transports cysteinesulfinate in exchange for either aspartate or glutamate |
| GO:0000515 aspartate:glutamate, proton antiporter activity | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct assay (IDA) demonstrating electrogenic aspartate/glutamate + H+ exchange by recombinant human aralar1 reconstituted into liposomes. This is the primary, defining molecular function of SLC25A12. Reason: Core molecular function directly demonstrated in a reconstituted transport assay. Supporting Evidence: PMID:11566871 catalyze the electrogenic exchange of aspartate for |
| GO:0000515 aspartate:glutamate, proton antiporter activity | IDA PMID:24515575 AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelinat... | ACCEPT | Summary: Direct assay (IDA) of aspartate:glutamate antiporter activity; the R353Q disease mutant retained only ~15% of wild-type activity, confirming the core function. Reason: Core molecular function; disease mutant abrogates activity. Supporting Evidence: PMID:24515575 AGC1 activity was reduced to 15% of |
| GO:0005739 mitochondrion | IDA PMID:19641205 AGC1 deficiency associated with global cerebral hypomyelinat... | KEEP AS NON CORE | Summary: Direct localization to mitochondrion. Correct but less specific than the inner-membrane localization annotated from the same and related studies. Reason: Accurate general parent of the mitochondrial inner membrane location. |
| GO:0005739 mitochondrion | IDA PMID:24515575 AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelinat... | KEEP AS NON CORE | Summary: Direct localization to mitochondrion. Correct but less specific than the experimentally supported inner-membrane localization. Reason: Accurate general parent of the mitochondrial inner membrane location. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct localization to the mitochondrial inner membrane, consistent with the multi-pass carrier topology. Core location. Reason: Experimentally supported core location. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0015810 aspartate transmembrane transport | IDA PMID:19641205 AGC1 deficiency associated with global cerebral hypomyelinat... | ACCEPT | Summary: Direct evidence for aspartate transmembrane transport (the aspartate-efflux half of the antiport); disease mutant abolishes it. Part of the core transport function. Reason: Component of the demonstrated aspartate/glutamate antiport. Supporting Evidence: PMID:19641205 supplies aspartate to the cytosol |
| GO:0015810 aspartate transmembrane transport | IDA PMID:24515575 AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelinat... | ACCEPT | Summary: Direct evidence for aspartate transmembrane transport, reduced by the R353Q disease mutation. Part of the core transport function. Reason: Component of the demonstrated aspartate/glutamate antiport. Supporting Evidence: PMID:24515575 AGC1 activity was reduced to 15% of |
| GO:0015813 L-glutamate transmembrane transport | IDA PMID:19641205 AGC1 deficiency associated with global cerebral hypomyelinat... | ACCEPT | Summary: Direct evidence for L-glutamate transmembrane transport (glutamate-uptake half of the antiport); abolished by the Q590R disease mutant. Part of the core function. Reason: Component of the demonstrated aspartate/glutamate antiport. Supporting Evidence: PMID:19641205 showed abolished activity |
| GO:0015813 L-glutamate transmembrane transport | IDA PMID:24515575 AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelinat... | ACCEPT | Summary: Direct evidence for L-glutamate transmembrane transport, reduced by the R353Q disease mutation. Part of the core transport function. Reason: Component of the demonstrated aspartate/glutamate antiport. Supporting Evidence: PMID:24515575 AGC1 activity was reduced to 15% of |
| GO:0005509 calcium ion binding | IDA PMID:25410934 Calcium-induced conformational changes of the regulatory dom... | ACCEPT | Summary: Direct structural demonstration of Ca2+ binding by the regulatory N-terminal domain; crystal structures show EF-hand 2 binds calcium. A genuine secondary molecular function that gates transport. Reason: Experimentally established Ca2+ binding via EF-hand 2; regulates carrier activity. Supporting Evidence: PMID:25410934 Only EF-hand 2 binds calcium |
| GO:0042802 identical protein binding | IDA PMID:25410934 Calcium-induced conformational changes of the regulatory dom... | ACCEPT | Summary: Direct evidence (SEC-MALLS and crystal structure) that the full-length carrier is a homodimer, mediated by the N-terminal domain. This informatively captures the self-association that generic "protein binding" does not. Reason: Experimentally demonstrated homodimerization. Supporting Evidence: PMID:25410934 form a twofold symmetrical homodimer file:human/SLC25A12/SLC25A12-uniprot.txt Homodimer (via N-terminus). |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | KEEP AS NON CORE | Summary: High-throughput (HDA) proteomic localization to mitochondrion. Correct but less specific than the inner-membrane localization. Reason: Accurate general parent of the mitochondrial inner membrane location. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-372448 | ACCEPT | Summary: Reactome traceable-author-statement placing the carrier in the mitochondrial inner membrane (SLC25A12,13 exchange L-Glu and L-Asp). Consistent with the core location. Reason: Correct core location, corroborated by experimental annotations. Supporting Evidence: file:human/SLC25A12/SLC25A12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005509 calcium ion binding | IDA PMID:9722566 Molecular cloning of Aralar, a new member of the mitochondri... | ACCEPT | Summary: Direct evidence (45Ca2+ overlay, calcium-dependent mobility shift) that the N-terminal half of aralar binds calcium. Secondary molecular function. Reason: Experimentally demonstrated calcium binding via the EF-hand domain. Supporting Evidence: PMID:9722566 calcium by 45Ca2+ overlay and calcium-dependent mobility shift assays |
| GO:0005739 mitochondrion | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | KEEP AS NON CORE | Summary: Direct localization to mitochondrion. Correct but less specific than the inner-membrane localization annotated from the same study. Reason: Accurate general parent of the mitochondrial inner membrane location. |
| GO:0005739 mitochondrion | IDA PMID:9722566 Molecular cloning of Aralar, a new member of the mitochondri... | KEEP AS NON CORE | Summary: Direct localization to mitochondrion (exclusively mitochondrial in transfected COS cells). Correct but less specific than inner-membrane localization. Reason: Accurate general parent of the mitochondrial inner membrane location. |
| GO:0015810 aspartate transmembrane transport | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct evidence for aspartate transmembrane transport in reconstituted liposomes, the aspartate-efflux half of the electrogenic antiport. Part of the core function. Reason: Component of the demonstrated aspartate/glutamate antiport. Supporting Evidence: PMID:11566871 catalyze the electrogenic exchange of aspartate for |
| GO:0015813 L-glutamate transmembrane transport | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct evidence for L-glutamate transmembrane transport in reconstituted liposomes, the glutamate-uptake half of the antiport. Part of the core function. Reason: Component of the demonstrated aspartate/glutamate antiport. Supporting Evidence: PMID:11566871 catalyze the electrogenic exchange of aspartate for |
| GO:0016020 membrane | NAS PMID:9722566 Molecular cloning of Aralar, a new member of the mitochondri... | KEEP AS NON CORE | Summary: Non-traceable author statement placing the protein in membrane. Correct but far less specific than the mitochondrial inner-membrane localization now established. Reason: Uninformative general location; superseded by inner-membrane annotations. |
| GO:0043490 malate-aspartate shuttle | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct evidence that aralar operates in the malate-aspartate NADH shuttle: overexpression in human cells increased shuttle activity. Core biological process. Reason: Directly demonstrated role in the malate-aspartate shuttle. Supporting Evidence: PMID:11566871 increased the activity of the malate/aspartate NADH shuttle |
| GO:0051592 response to calcium ion | IDA PMID:11566871 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate... | ACCEPT | Summary: Direct evidence that transport activity is stimulated by external Ca2+ acting on the regulatory domain in the intermembrane space. A genuine (non-core) regulatory response reflecting the carrier's Ca2+ dependence. Reason: Ca2+-stimulated transport activity is experimentally established. Supporting Evidence: PMID:11566871 was stimulated by Ca 2+ on the external side of |
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