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.
Summary: TNF receptor activity is the defining function of TNFR1, but this sequence lacks part of the ligand-binding ectodomain.
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.
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.
Summary: Inflammatory response is a downstream outcome of TNFR1 signalling; it depends on ligand-induced activation that is uncertain for this truncated model.
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.
Summary: Signal transduction is inferred from the death domain, which is intact in this donkey sequence.
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.
Summary: TNF-mediated signaling pathway is inferred from the receptor-activity row; it requires TNF binding, which is uncertain for this model.
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.
Summary: TNF binding requires the cysteine-rich ectodomain, part of which is missing from this sequence.
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.
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.
Summary: Signaling receptor complex reflects ligand-induced and PLAD-mediated receptor assembly; the PLAD-containing CRD1 is partly missing here.
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.
Summary: Membrane raft localization is reported for TNFR1 and depends on the membrane-anchored receptor, which this model retains.
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.
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.
Q: 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
Experiment: 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.
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of 2 ProtNLM2 GO predictions for donkey TNFRSF1A (A0A9L0JKX4), the 410-aa product of an exon-3-skipping alternative Ensembl transcript of the TNFRSF1A gene; 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 domain 2 (human residues 64-106), while the signal peptide, transmembrane segment and death domain are retained. Membrane is correct but less precise than the plasma membrane, Golgi membrane and membrane raft annotations the gene already carries (LSP). Signal transduction is correct for the retained death-domain module and is already in GOA on this product (CNN). Both predictions are generic and avoid the ligand-binding claims that are uncertain for this truncated ectodomain. A PubMed search for equine or donkey TNFR1 found no study of this transcript variant. ProtNLM2 also emitted non-GO subcellular locations "Cell membrane", "Membrane" and "Golgi apparatus membrane" for this accession, which are not scored here.
LSP — Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: The donkey model keeps the signal peptide and a single transmembrane segment (172-194), and human TNFR1 is a single-pass type I cell-membrane and Golgi-membrane protein, so membrane is correct. GOA for this product carries membrane raft (kept as non-core in the gene review), and the canonical product A0A8C4MD74 of the same gene carries plasma membrane (accepted in its review) and Golgi membrane; all are GO descendants of membrane, so the prediction is correct but less precise than existing annotations.
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: The cytoplasmic death domain (311-396) is retained and aligns without gaps to the human TNFR1 death domain, which nucleates TRADD recruitment and downstream NF-kappaB and apoptotic signalling. Signal transduction is therefore correct for this protein even though its ligand-binding ectodomain is internally truncated (exon 3 skipped). The exact term is already in GOA for this product (InterPro2GO from the death domain) and is accepted in the gene review; the more specific TNF-mediated signaling pathway row is UNDECIDED there because ligand binding is uncertain, so CNN rather than LSP is used.