id: A0A9L0JKX4 gene_symbol: TNFRSF1A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9793 label: Equus asinus description: TNFRSF1A (TNF receptor 1, p55/p60, CD120a) is a type I transmembrane receptor of the TNF receptor superfamily. In mammals its extracellular region of four cysteine-rich domains binds trimeric TNF and lymphotoxin-alpha, and its cytoplasmic death domain recruits TRADD, which scaffolds membrane-proximal complexes activating NF-kappaB and MAPK pathways or, when these fail, caspase-8-dependent apoptosis and necroptosis; it is a central mediator of inflammatory signalling. This donkey entry (410 aa) is the product of an alternative Ensembl transcript of the TNFRSF1A gene that skips coding exon 3 (43 codons, in frame); it is otherwise identical to the 453-aa canonical donkey product (A0A8C4MD74). The skipped exon encodes the second half of cysteine-rich domain 1 and most of cysteine-rich domain 2, so this variant retains the signal peptide, the membrane-proximal cysteine-rich region, the transmembrane segment and the death domain, but whether it binds TNF, and whether the transcript is expressed, is unknown. existing_annotations: - term: id: GO:0005031 label: tumor necrosis factor receptor activity evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: enables supporting_entities: - PANTHER:PTN001499618 review: summary: TNF receptor activity is the defining function of TNFR1, but this sequence lacks part of the ligand-binding ectodomain. action: UNDECIDED reason: This donkey sequence model lacks the region aligned to human residues 64-106 (second half of TNFR-Cys 1 and most of TNFR-Cys 2, including the 62-81 and 84-99 disulfides), and UniProt flags missing conserved TNFR-Cys residues. Human TNFR1 binds TNF through its elongated four-domain ectodomain, so whether this truncated ectodomain still binds TNF is unknown. The term was placed by PAINT at the Euteleostomi TNFRSF1A node (PTN002930098) from experimental data on human or mouse TNFR1, and is correct for the canonical donkey product A0A8C4MD74; this entry differs from it only by skipping coding exon 3, so it inherits the term at the gene level but the ligand-binding claim cannot be confirmed for this splice-variant model. supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md supporting_text: '- human residues 64-106.' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: 'Deleted block (A0A8C4MD74 positions 65-107): GTYLHNDCLGPGLDTDCRECENGTFTASENHLRQCLSCSKCRK' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-uniprot.txt record_section: ["CC:CAUTION"] supporting_text: Lacks conserved residue(s) required for the propagation of feature annotation. - reference_id: PMID:8387891 supporting_text: The receptor fragment, a very elongated end to end assembly of four similar folding domains, binds in the groove between two adjacent TNF beta subunits. - term: id: GO:0006954 label: inflammatory response evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001499618 review: summary: Inflammatory response is a downstream outcome of TNFR1 signalling; it depends on ligand-induced activation that is uncertain for this truncated model. action: UNDECIDED reason: For the TNFRSF1A gene this is a well-supported process (accepted in the human review). This donkey sequence model lacks the region aligned to human residues 64-106 (second half of TNFR-Cys 1 and most of TNFR-Cys 2, including the 62-81 and 84-99 disulfides), and UniProt flags missing conserved TNFR-Cys residues. Human TNFR1 binds TNF through its elongated four-domain ectodomain, so whether this truncated ectodomain still binds TNF is unknown. The term was placed by PAINT at the Euteleostomi TNFRSF1A node (PTN002930098) from experimental data on human or mouse TNFR1, and is correct for the canonical donkey product A0A8C4MD74; this entry differs from it only by skipping coding exon 3, so it inherits the term at the gene level but the ligand-binding claim cannot be confirmed for this splice-variant model. supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md supporting_text: '- human residues 64-106.' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: 'Deleted block (A0A8C4MD74 positions 65-107): GTYLHNDCLGPGLDTDCRECENGTFTASENHLRQCLSCSKCRK' - term: id: GO:0007165 label: signal transduction evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR000488 review: summary: Signal transduction is inferred from the death domain, which is intact in this donkey sequence. action: ACCEPT reason: The cytoplasmic death domain (donkey 311-396) that nucleates TRADD binding is retained, so the protein retains the intracellular signalling module. The term is broad but is the most specific process that can be asserted for this sequence model, since the TNF-mediated pathway is undecided because ligand binding is uncertain. supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-uniprot.txt record_section: ["DR:InterPro"] supporting_text: IPR033994; TNFRSF1A_death - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. - term: id: GO:0033209 label: tumor necrosis factor-mediated signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: involved_in supporting_entities: - GO:0005031 review: summary: TNF-mediated signaling pathway is inferred from the receptor-activity row; it requires TNF binding, which is uncertain for this model. action: UNDECIDED reason: Correct for the TNFRSF1A gene. This donkey sequence model lacks the region aligned to human residues 64-106 (second half of TNFR-Cys 1 and most of TNFR-Cys 2, including the 62-81 and 84-99 disulfides), and UniProt flags missing conserved TNFR-Cys residues. Human TNFR1 binds TNF through its elongated four-domain ectodomain, so whether this truncated ectodomain still binds TNF is unknown. This row is a GO_REF:0000108 inference from the TreeGrafter receptor-activity row (PAINT itself did not place this process at the TNFRSF1A node PTN002930098), and is correct for the canonical donkey product A0A8C4MD74; this entry differs from it only by skipping coding exon 3, so it inherits the term at the gene level but the ligand-binding claim cannot be confirmed for this splice-variant model. supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md supporting_text: '- human residues 64-106.' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: 'Deleted block (A0A8C4MD74 positions 65-107): GTYLHNDCLGPGLDTDCRECENGTFTASENHLRQCLSCSKCRK' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-uniprot.txt record_section: ["CC:CAUTION"] supporting_text: Lacks conserved residue(s) required for the propagation of feature annotation. - term: id: GO:0043120 label: tumor necrosis factor binding evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: enables supporting_entities: - PANTHER:PTN001499618 review: summary: TNF binding requires the cysteine-rich ectodomain, part of which is missing from this sequence. action: UNDECIDED reason: This donkey sequence model lacks the region aligned to human residues 64-106 (second half of TNFR-Cys 1 and most of TNFR-Cys 2, including the 62-81 and 84-99 disulfides), and UniProt flags missing conserved TNFR-Cys residues. Human TNFR1 binds TNF through its elongated four-domain ectodomain, so whether this truncated ectodomain still binds TNF is unknown. The term was placed by PAINT at the Euteleostomi TNFRSF1A node (PTN002930098) from experimental data on human or mouse TNFR1, and is correct for the canonical donkey product A0A8C4MD74; this entry differs from it only by skipping coding exon 3, so it inherits the term at the gene level but the ligand-binding claim cannot be confirmed for this splice-variant model. supported_by: - reference_id: PMID:8387891 supporting_text: The receptor fragment, a very elongated end to end assembly of four similar folding domains, binds in the groove between two adjacent TNF beta subunits. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md supporting_text: '- human residues 64-106.' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: 'Deleted block (A0A8C4MD74 positions 65-107): GTYLHNDCLGPGLDTDCRECENGTFTASENHLRQCLSCSKCRK' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-uniprot.txt record_section: ["CC:CAUTION"] supporting_text: Lacks conserved residue(s) required for the propagation of feature annotation. - term: id: GO:0043235 label: signaling receptor complex evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: part_of supporting_entities: - PANTHER:PTN001499618 review: summary: Signaling receptor complex reflects ligand-induced and PLAD-mediated receptor assembly; the PLAD-containing CRD1 is partly missing here. action: UNDECIDED reason: Human TNFR1 trimerizes on TNF binding and recruits TRADD-based complexes. With half of CRD1 and most of CRD2 absent, ligand-dependent assembly of this protein cannot be inferred with confidence. Correct for the gene. supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: Binding of TNF to the extracellular domain leads to homotrimerization. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md supporting_text: '- human residues 64-106.' - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: 'Deleted block (A0A8C4MD74 positions 65-107): GTYLHNDCLGPGLDTDCRECENGTFTASENHLRQCLSCSKCRK' - term: id: GO:0045121 label: membrane raft evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN001499618 review: summary: Membrane raft localization is reported for TNFR1 and depends on the membrane-anchored receptor, which this model retains. action: KEEP_AS_NON_CORE reason: The donkey protein keeps the signal peptide and transmembrane segment; TNFR1 partitions into lipid rafts in mammalian cells (IBA accepted in the human review). Non-core localization detail beyond plasma membrane. supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt supporting_text: Cell membrane {ECO:0000269|PubMed:22801493} - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-uniprot.txt record_section: ["FT:TRANSMEM"] supporting_text: TRANSMEM 172..194 references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: GO_REF:0000118 title: TreeGrafter-generated GO annotations findings: [] - id: PMID:22801493 title: TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Cached full text; source of the human cell-membrane localization in UniProt; describes TNFR1 isoforms and surface trimerization. - id: PMID:8387891 title: 'Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation.' findings: - statement: The four-domain TNFR1 ectodomain binds in the groove between adjacent TNF-beta subunits. supporting_text: The receptor fragment, a very elongated end to end assembly of four similar folding domains, binds in the groove between two adjacent TNF beta subunits. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached abstract only; does not map contacts to individual cysteine-rich domains. - id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt title: UniProtKB Swiss-Prot record P19438 (human TNFRSF1A), fetched 2026-10-14 findings: [] - id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md title: 'TNFRSF1A: donkey-human sequence comparison' findings: [] - id: file:EQUAS/TNFRSF1A/TNFRSF1A-uniprot.txt title: UniProtKB record A0A9L0JKX4 (donkey TNFRSF1A) findings: [] - id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md title: 'TNFRSF1A (donkey): comparison of the two gene models' findings: - statement: A0A9L0JKX4 is the exon-3-skipping alternative transcript product of the donkey TNFRSF1A gene; otherwise identical to the canonical 453-aa product A0A8C4MD74. supporting_text: 'The 410-aa transcript lacks exactly one exon of the canonical transcript: exon 3 (ENSEASE00005153555, 129 nt = 43 codons, in frame).' core_functions: - description: Membrane-anchored TNFR1-family receptor whose conserved cytoplasmic death domain recruits TRADD-based signalling complexes; in the canonical receptor this signalling is triggered by TNF binding to the cysteine-rich ectodomain, which is internally truncated in this sequence model. directly_involved_in: - id: GO:0007165 label: signal transduction locations: - id: GO:0005886 label: plasma membrane supported_by: - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/human_P19438-uniprot.txt supporting_text: Cell membrane {ECO:0000269|PubMed:22801493} - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS.md supporting_text: aligns to human P19438 (455 residues) with 74.32% identity across 405 paired residues - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: The skipped exon encodes the C-terminal half of the first cysteine-rich domain and most of the second - reference_id: file:EQUAS/TNFRSF1A/TNFRSF1A-bioinformatics/RESULTS-rereview.md supporting_text: Both UniProt entries map to the same Ensembl gene, so A0A9L0JKX4 is an exon-3-skipping alternative suggested_questions: - question: Is the exon-3-skipped donkey TNFRSF1A transcript encoding A0A9L0JKX4 (lacking the segment equivalent to human TNFR1 residues 64-106) genuinely expressed, and can its product bind TNF or act as a dominant-negative receptor? suggested_experiments: - description: RT-PCR across the TNFRSF1A exons encoding cysteine-rich domains 1-2 in donkey tissues, and TNF binding assays on the expressed 410-aa ectodomain compared with the full-length receptor.