id: Q9BTE6 gene_symbol: AARSD1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- AARSD1 encodes a conserved AlaX-family trans-editing factor that functions in the cytoplasm to hydrolyze mischarged aminoacyl-tRNAs and preserve translational fidelity. The literature and UniProt support AARSD1 as a proofreading enzyme rather than an alanine-tRNA ligase. Recent direct work on human AlaX shows broad activity against Ser-mischarged tRNAs and links AARSD1 loss to Ala- and Thr-to-Ser mistranslation, supporting a translation-quality-control role as core biology. A proposed HSP90 cochaperone interpretation is not supported as a core gene-level assignment for canonical AARSD1; the relevant muscle-differentiation paper appears to map to non-canonical readthrough-derived PTGES3L-AARSD1 fusion isoforms noted by UniProt for isoforms 2 and 3. That HSP90-related role is best treated as contextual and isoform-associated rather than a general function of canonical AARSD1. aliases: - AlaXp alternative_products: - name: "1" id: Q9BTE6-1 - name: "2" id: Q9BTE6-2 sequence_note: VSP_023014 - name: "3" id: Q9BTE6-3 sequence_note: VSP_043142 functional_isoforms: - id: AARSD1_ALAX name: canonical AlaX isoform type: SPLICE_VARIANT maps_to: - type: UNIPROT_ISOFORM ids: - Q9BTE6-1 description: >- Canonical AARSD1 proofreading isoform. This cytoplasmic AlaX protein is the best-supported form for aminoacyl-tRNA deacylase activity and translational fidelity maintenance. PMID:38869066 shows that human AlaX is exclusively cytoplasmic and acts as a Ser-selective trans-editing factor whose loss increases mistranslation. isoform_specific_terms: - id: GO:0002161 label: aminoacyl-tRNA deacylase activity - id: GO:0106074 label: aminoacyl-tRNA metabolism involved in translational fidelity - id: AARSD1_READTHROUGH_FUSION name: readthrough-derived fusion isoforms type: SPLICE_CLASS maps_to: - type: UNIPROT_ISOFORM ids: - Q9BTE6-2 - Q9BTE6-3 description: >- Non-canonical forms that UniProt notes are based on readthrough transcripts that may produce a PTGES3L-AARSD1 fusion protein. The muscle HSP90 cochaperone literature on Aarsd1L/Aarsd1S likely applies to this fusion-like class rather than to canonical AARSD1. Any HSP90 cochaperone role should therefore be kept separate from the conserved AlaX proofreading function. existing_annotations: - term: id: GO:0002196 label: Ser-tRNA(Ala) deacylase activity evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: >- This phylogenetically inferred annotation matches the now directly supported core activity of human AARSD1/AlaX. Human AlaX is a Ser-selective trans-editing factor, and Ser-tRNA(Ala) deacylation remains the defining conserved function of the AlaX family. action: ACCEPT reason: >- Appropriate core molecular-function annotation for canonical AARSD1. supported_by: - reference_id: PMID:38869066 supporting_text: human AlaX (hAlaX), which is exclusively distributed in the cytoplasm, is an active trans-editing factor with strict Ser-specificity - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala). - term: id: GO:0006450 label: regulation of translational fidelity evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: >- AARSD1 clearly participates in translational fidelity control by proofreading mischarged tRNAs. The term is broader than the mechanistic process term GO:0106074, but it remains biologically true. action: ACCEPT reason: >- Supported parent-level process annotation for the gene's proofreading role. supported_by: - reference_id: PMID:38869066 supporting_text: loss of ScAlaX or hAlaX readily induced Ala- and Thr-to-Ser misincorporation - reference_id: PMID:38869066 supporting_text: provide multiple checkpoints to maintain the speed and fidelity of genetic decoding - reference_id: file:human/AARSD1/AARSD1-deep-research-falcon.md supporting_text: AARSD1/hAlaX is positioned in a translation quality-control pathway that prevents (or reduces) amino acid misincorporation - term: id: GO:0106074 label: aminoacyl-tRNA metabolism involved in translational fidelity evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: >- This is the most mechanistically informative biological-process term among the existing translation-quality-control annotations. AARSD1 removes incorrect amino acids from charged tRNAs after aminoacylation, matching the term definition. action: ACCEPT reason: >- Directly supported by recent human AlaX work and consistent with UniProt curation. supported_by: - reference_id: PMID:38869066 supporting_text: In vitro, both hAlaX and yeast AlaX (ScAlaX) were capable of hydrolyzing nearly all Ser-mischarged cytoplasmic and mitochondrial tRNAs - reference_id: PMID:38869066 supporting_text: provide multiple checkpoints to maintain the speed and fidelity of genetic decoding - reference_id: file:human/AARSD1/AARSD1-deep-research-falcon.md supporting_text: hydrolyzes mischarged aa-tRNAs (especially serine-mischarged tRNAs) to protect proteome fidelity and modulate decoding dynamics - term: id: GO:0002161 label: aminoacyl-tRNA deacylase activity evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: >- The generic deacylase term is appropriate because human AlaX has broader activity than only Ser-tRNA(Ala) hydrolysis and acts on multiple Ser-mischarged tRNA species in the 2024 human study. action: ACCEPT reason: >- Supported core molecular function and a good summary term for the expanded substrate range of eukaryotic AlaX. supported_by: - reference_id: PMID:38869066 supporting_text: active trans-editing factor with strict Ser-specificity - reference_id: PMID:38869066 supporting_text: hydrolyzing nearly all Ser-mischarged cytoplasmic and mitochondrial tRNAs - reference_id: file:human/AARSD1/AARSD1-deep-research-falcon.md supporting_text: The best-supported primary biochemical function of human AARSD1 is deacylation (hydrolysis) of misacylated aa-tRNAs - term: id: GO:0002196 label: Ser-tRNA(Ala) deacylase activity evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- The orthology-transferred annotation is consistent with both the conserved AlaX family assignment and direct human evidence. action: ACCEPT reason: >- Correct orthology-supported annotation for canonical AARSD1. supported_by: - reference_id: PMID:38869066 supporting_text: active trans-editing factor with strict Ser-specificity - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala). - term: id: GO:0000166 label: nucleotide binding evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- This InterPro-derived annotation appears to conflate AARSD1 with catalytic alanine-tRNA synthetases. The canonical human protein is an AlaX editing factor rather than a nucleotide-dependent ligase, and current curated sources emphasize proofreading plus zinc binding rather than nucleotide binding. action: REMOVE reason: >- No convincing evidence for a standalone nucleotide-binding function of canonical AARSD1. supported_by: - reference_id: PMID:38869066 supporting_text: active trans-editing factor with strict Ser-specificity - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala). - term: id: GO:0003676 label: nucleic acid binding evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- AARSD1 necessarily contacts tRNA substrates, but this generic term is far less informative than the specific deacylase activities already present. The annotation adds little biological value and blurs the actual proofreading function. action: MARK_AS_OVER_ANNOTATED reason: >- Substrate binding is implicit in the catalytic proofreading activity; generic nucleic acid binding is too broad for this gene. supported_by: - reference_id: PMID:38869066 supporting_text: hydrolyzing nearly all Ser-mischarged cytoplasmic and mitochondrial tRNAs - term: id: GO:0004812 label: aminoacyl-tRNA ligase activity evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- This is a domain/family-based overcall from the gene name and remote synthetase homology. Canonical AARSD1 lacks the core aminoacylation role of AARS1 and is instead an editing enzyme that acts in trans after aminoacylation. action: REMOVE reason: >- Incorrect molecular-function assignment for canonical AARSD1. supported_by: - reference_id: PMID:38869066 supporting_text: The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala). - term: id: GO:0004813 label: alanine-tRNA ligase activity evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- This is even more specifically incorrect than GO:0004812. The alanine-charging enzyme is AARS1, whereas AARSD1 is the trans-editing AlaX factor that proofreads mischarged tRNAs. action: REMOVE reason: >- Not supported for canonical AARSD1; this annotation conflates editing with aminoacylation. supported_by: - reference_id: PMID:38869066 supporting_text: The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala). - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- ATP binding is inferred here from the same mistaken synthetase-like propagation that produced the ligase annotations. Neither UniProt nor the direct human AlaX study supports ATP-dependent aminoacylation as a function of canonical AARSD1. action: REMOVE reason: >- Likely a false positive carried over from aaRS homology rather than an authentic activity of AARSD1. supported_by: - reference_id: PMID:38869066 supporting_text: active trans-editing factor with strict Ser-specificity - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Name=Zn(2+) - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: >- Cytoplasmic localization is strongly supported and fits the proofreading role of canonical AARSD1 in cytoplasmic translation quality control. action: ACCEPT reason: >- Best-supported core localization for the canonical protein. supported_by: - reference_id: PMID:38869066 supporting_text: human AlaX (hAlaX), which is exclusively distributed in the cytoplasm - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm" - term: id: GO:0006419 label: alanyl-tRNA aminoacylation evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- This annotation incorrectly assigns the aminoacylation step itself to AARSD1. The protein functions downstream as a proofreading factor and does not charge tRNA with alanine. action: REMOVE reason: >- AARSD1 maintains fidelity after aminoacylation rather than catalyzing alanine charging. supported_by: - reference_id: PMID:38869066 supporting_text: The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla - reference_id: PMID:32484512 supporting_text: while wrong amino acids are corrected within an aaRS, a wrong tRNA is handled in trans by an aaRS cognate to the mischarged tRNA species - term: id: GO:0043039 label: tRNA aminoacylation evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- As with the alanine-specific process term above, this broader aminoacylation annotation conflates proofreading with the charging reaction itself. action: REMOVE reason: >- Canonical AARSD1 is a trans-editing factor, not an aminoacyl-tRNA synthetase. supported_by: - reference_id: PMID:38869066 supporting_text: The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla - term: id: GO:0005634 label: nucleus evidence_type: HDA original_reference_id: PMID:21630459 review: summary: >- The evidence is a high-throughput proteomic characterization of purified human sperm nuclei, not a focused localization study of canonical AARSD1 in typical somatic cells. This makes the nuclear call plausible as a specialized context but not part of the core localization/function profile of the gene. action: KEEP_AS_NON_CORE reason: >- Keep as a context-specific observation only; the canonical and directly tested localization remains cytoplasmic. supported_by: - reference_id: PMID:21630459 supporting_text: 403 different proteins have been identified from the isolated sperm nuclei - reference_id: PMID:38869066 supporting_text: human AlaX (hAlaX), which is exclusively distributed in the cytoplasm - term: id: GO:0003674 label: molecular_function evidence_type: ND original_reference_id: GO_REF:0000015 review: summary: >- This placeholder annotation reflected the absence of curated function at an earlier stage and is now obsolete. action: REMOVE reason: >- AARSD1 has directly supported proofreading activities and no longer requires an ND placeholder. - term: id: GO:0008150 label: biological_process evidence_type: ND original_reference_id: GO_REF:0000015 review: summary: >- This placeholder annotation is obsolete because AARSD1 now has well-supported biological-process assignments tied to translational fidelity. action: REMOVE reason: >- Replace generic ND with the supported translation-quality-control terms above. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000015 title: Use of the ND evidence code for Gene Ontology (GO) terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:21630459 title: Proteomic characterization of the human sperm nucleus. findings: [] - id: PMID:26884463 title: A Remodeled Hsp90 Molecular Chaperone Ensemble with the Novel Cochaperone Aarsd1 Is Required for Muscle Differentiation. findings: [] - id: PMID:32484512 title: Cross-editing by a tRNA synthetase allows vertebrates to abundantly express mischargeable tRNA without causing mistranslation. findings: [] - id: PMID:38869066 title: Eukaryotic AlaX provides multiple checkpoints for quality and quantity of aminoacyl-tRNAs in translation. findings: [] - id: UniProt:Q9BTE6 title: UniProt record for AARSD1 (Q9BTE6) findings: [] - id: file:human/AARSD1/AARSD1-uniprot.txt title: UniProt text export for AARSD1 (Q9BTE6) findings: [] - id: file:human/AARSD1/AARSD1-deep-research-falcon.md title: Falcon deep research report for AARSD1 findings: - statement: Falcon research supports AARSD1 as a cytoplasmic AlaX trans-editing factor that deacylates serine-mischarged tRNAs to preserve translational fidelity. supporting_text: AARSD1/hAlaX is such a free-standing, cytoplasmic trans-editing factor - id: file:human/AARSD1/AARSD1-hypotheses/alax-editing-residues-vs-hsp90/openscientist.md title: 'OpenScientist hypothesis run: AARSD1 AlaX editing residues vs HSP90' findings: - statement: Confirms AARSD1 is a bona fide AlaX trans-editing deacylase - all four zinc-binding catalytic residues (H109/H113/C209/H213) are present with AlphaFold Zn coordination of 2.0-2.4 Angstroms - and that the HSP90-cochaperone association is a readthrough/fusion-isoform artifact that should not be annotated as an intrinsic AARSD1 function. supporting_text: the HSP90 cochaperone association is a readthrough artifact and should not be annotated as an intrinsic function. core_functions: - description: Cytoplasmic trans-editing proofreading of Ser-mischarged aminoacyl-tRNAs to preserve translational fidelity. molecular_function: id: GO:0002161 label: aminoacyl-tRNA deacylase activity directly_involved_in: - id: GO:0106074 label: aminoacyl-tRNA metabolism involved in translational fidelity - id: GO:0006450 label: regulation of translational fidelity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:38869066 supporting_text: active trans-editing factor with strict Ser-specificity - reference_id: PMID:38869066 supporting_text: loss of ScAlaX or hAlaX readily induced Ala- and Thr-to-Ser misincorporation - reference_id: file:human/AARSD1/AARSD1-deep-research-falcon.md supporting_text: AARSD1/hAlaX is positioned in a translation quality-control pathway that prevents (or reduces) amino acid misincorporation - description: Canonical AlaX proofreading of Ser-tRNA(Ala) as a conserved substrate-specific activity within translation quality control. molecular_function: id: GO:0002196 label: Ser-tRNA(Ala) deacylase activity directly_involved_in: - id: GO:0106074 label: aminoacyl-tRNA metabolism involved in translational fidelity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:38869066 supporting_text: The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla - reference_id: file:human/AARSD1/AARSD1-uniprot.txt supporting_text: Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala). - reference_id: file:human/AARSD1/AARSD1-deep-research-falcon.md supporting_text: Human AARSD1 (hAlaX) is described as predominantly hydrolyz[ing] Ser-tRNAAla proposed_new_terms: [] suggested_questions: - question: Does human muscle primarily express the canonical AARSD1 proofreading isoform, PTGES3L-AARSD1 readthrough fusion proteins, or both under differentiation conditions? - question: Is the sperm-nuclear detection of AARSD1 a true specialized localization or a context-dependent carryover from highly abundant translation-quality-control machinery? - question: Which endogenous mischarged human tRNA species dominate AARSD1 dependence in vivo outside the cell systems tested in PMID:38869066? suggested_experiments: - description: Isoform-specific long-read RNA-seq plus targeted proteomics in human skeletal muscle and differentiating myoblasts to distinguish canonical AARSD1 from PTGES3L-AARSD1 readthrough products. experiment_type: transcriptomics/proteomics hypothesis: The reported HSP90-cochaperone activity maps to readthrough-derived fusion isoforms rather than to canonical AARSD1. - description: CRISPR knockout or degron depletion of canonical AARSD1 followed by mistranslation proteomics to quantify Ala- and Thr-to-Ser substitutions in human cells. experiment_type: genetic manipulation/proteomics hypothesis: Loss of canonical AARSD1 increases specific serine misincorporation events predicted from AlaX proofreading defects. - description: Endogenous isoform-resolved localization of canonical AARSD1 and readthrough-derived fusion proteins in sperm and somatic cells using isoform-specific tagging or proteotypic peptides. experiment_type: microscopy/proteomics hypothesis: Canonical AARSD1 is predominantly cytoplasmic, whereas any nuclear or HSP90-associated signal is restricted to specialized contexts or readthrough-derived isoforms.