CR2

Summary: CR2 is an established Epstein–Barr virus attachment and entry receptor.

Reason: The cloning source identifies the human B-cell EBV/C3d receptor, and the separate gp350/220 experiments establish receptor-mediated adsorption, capping and endocytosis. Retain the positive virus-receptor role as a host-exploitation context distinct from the complement/B-cell signaling core. The historical cloning construct is not silently assigned to every current splice product.

Summary: The C3-fragment binding assertion includes directly tested iC3b.

Reason: The complete abstract describes alanine substitutions in the C3d region tested in mutant iC3b molecules for CR2 binding. Both the complement-product identity and positive binding are explicit. Retain the broader complement-binding term across this actual ligand context; the finer C3d co-crystal assertions are evaluated separately. Full original Methods were not recovered, so detailed construct and affinity claims defer to the experimental curator.

Summary: The electronic complement-binding assignment matches the established ligand class.

Reason: Current ARBA00091660 branch 1 matches the official target identifiers and taxonomy. Independent C3-fragment binding and structural evidence supports the biological assertion. This current applicability check is not a reconstruction of the historical rule execution.

Summary: Complement receptor activity entails the corresponding receptor-mediated signaling pathway.

Reason: The source uses the logical link from GO:0004875. CR2 binds complement fragments and supplies the ligand-recognition component of B-cell signaling complexes. Retain this existing inferred process at the receptor-signaling scope; it does not assign complement protease activity or every downstream immune response to CR2.

Summary: The actual ancestral T-cell immunity assertion is on the CR2 lineage, but its human target scope remains unclear.

Reason: The reconstructed current tree places human CR2 below PTN000448838 and its GO:0002456 IBD, with no target-path loss record. The CD46 descendant evidence is a legitimate curator premise, not weak support because of donor count. However, CR2-mediated B-cell responses requiring T-cell help do not by themselves demonstrate a process carried out by T cells. The target-specific participation interpretation remains unresolved, rather than contradicted.

Summary: Retain direct DNA binding at the tested soluble receptor-fragment and assay scope.

Reason: The full original Methods and Results test human SCR1–4 and soluble SCR1–15 constructs by ELISA and surface plasmon resonance with several DNA preparations and ligand/antibody competition. These are positive binding data, not a transcription-factor assay. The authors report ionic-strength dependence, no high-affinity interaction at 150 mM NaCl, and inability to reproduce CR2-specific cell-surface DNA binding reliably. Retain the broad positive DNA-binding activity without an intrinsic nuclear function, physiological affinity, or all-product equivalence claim.

Summary: The ARBA complement-receptor assertion agrees with established receptor function.

Reason: Current ARBA00087820 branch 0 matches the official human target. Ligand recognition together with B-cell signaling supports complement receptor activity. The parent term accommodates genuine C3d, C3dg and iC3b contexts; selecting only one ligand-specific child would incompletely summarize this electronic target-level assertion.

Summary: The historical complement-receptor identity is well supported.

Reason: The original cloning study purified and sequenced the human B-cell EBV/C3d receptor and reported its extracellular repeats and membrane anchor. Its receptor assignment is background/NAS rather than a modern signaling reconstitution, but independent binding and CD19-associated signaling studies establish the same function. Retain its source identity and historical product boundary.

Summary: Retain the traceable complement-receptor assignment.

Reason: The genomic organization study identifies the human C3d/EBV receptor; the available abstract concerns exon organization and polymorphisms rather than a new receptor-activation assay. Its TAS assignment is consistent with independently established human complement binding and B-cell signaling. Full original Methods were not recovered, so no assay is invented for this citation.

Summary: Retain the positive interferon-associated receptor activity as a contextual non-core function.

Reason: The original 1991 article establishes purified CR2/IFN-alpha binding, competition, cell binding and proliferation effects. Later work reports CR2 antibody-sensitive IFN-alpha-responsive gene induction in purified human B cells. These positive assays support retaining receptor activity in this interferon context as non-core, consistently with the companion GO:0060337 assertion, rather than refining it to complement receptor activity. The precise relationship to IFNAR1/IFNAR2 remains unresolved; neither source establishes that CR2 replaces those canonical receptors.

Summary: Specify complement receptor activity within the broader signaling-receptor assertion.

Reason: The historical cloning source identifies the C3d/EBV receptor. Independent human binding and CD19-associated signaling support GO:0004875 as a more informative receptor activity for this NAS assertion. Other positive ligand contexts remain separately represented; the refinement does not claim that complement is CR2’s only ligand class.

Proposed replacements: complement receptor activity

Summary: Specify binding to complement component C3d.

Reason: The source reports the CR2–C3d structural complex. The positive partner is the C3-derived C3d fragment, so GO:0001854 captures the demonstrated ligand more precisely than generic protein binding. Interface geometry must be distinguished from the existence of binding, and the original partner/source fields remain unchanged. This is a source-scoped binding refinement, not an added receptor-activation assay.

Proposed replacements: complement component C3d binding

Summary: Specify binding to the immunoglobulin receptor CD23.

Reason: The full original study measures human CD21 SCR1–2 binding to human CD23 by surface plasmon resonance and maps interactions by NMR. CD23 is the low-affinity IgE receptor, so GO:0034987 describes the demonstrated partner class. This does not mean that CR2 binds IgE directly, nor that the binding assay proves activation of CD23 or a new signaling mechanism. This source-specific refinement intentionally converges on the existing GO:0034987 IDA assertion from the same paper; the IPI source and its CD23 WITH/FROM remain distinct.

Proposed replacements: immunoglobulin receptor binding

Summary: Specify the C3d ligand in the positive structural binding assertion.

Reason: The human CR2–C3d co-crystal directly supports the C3d-binding class. GO:0001854 preserves that positive interaction with better ligand precision than GO:0005515. The changed interface relative to the earlier structure is not a contradiction of C3d binding; no equal activity of all four full-length splice products is inferred.

Proposed replacements: complement component C3d binding

Summary: Retain the positive interaction with the p120/HNRNPU protein at its reported scope.

Reason: The complete abstract maps p120 ribonucleoprotein interaction to a CR2 SCR4-derived sequence and distinguishes it from p53 and p68 binding at the cytoplasmic tail. The original partner Q00839 is HNRNPU. Full Methods were not recovered, and the suggested nuclear crosslinker mechanism is not demonstrated by the abstract. Retain the specific positive interaction without manufacturing an adaptor activity, transcriptional role, or an enzyme class from a domain label.

Summary: Retain extracellular CR2 occurrence without making secretion its defining topology.

Reason: The actual PTN008569518 extracellular-region IBD is on the human target path. Literal descendant records include rat Cr2 experimental evidence as well as C4BPA; the premise is not merely that CR2 has an ectodomain. Extracellular/exosomal occurrence is compatible with the membrane receptor, but does not imply that every product is freely secreted. The original human exosome target peptide table remains unavailable.

Summary: The ancestral plasma-membrane location is retained in human CR2.

Reason: PTN000448838 carries the current plasma-membrane IBD on the human target path, and the target MSA exactly matches the displayed 1033-residue sequence. The target’s own presence among descendant evidence is legitimate. Human surface-receptor and receptor-complex experiments independently support the same location; no target loss or lineage divergence was identified.

Summary: Human CR2 is detected in a cell-surface signaling complex.

Reason: The complete abstract reports CD19/CD21 immunoprecipitation, TAPA-1 identity verification, surface patching and signaling responses in B-cell and transfected K562 contexts. This supports plasma-membrane CR2. Full original Methods were not recovered; retain the experimental curator’s assertion without assigning detection to a particular current splice product.

Summary: The human CR2–CD19 membrane complex supports plasma-membrane localization.

Reason: The source reports reciprocal immunoprecipitation from Raji B-cell digitonin lysates and reconstitution with recombinant CR2/CD19 in K562 cells. These positive membrane-complex results support the stated location. The complete abstract distinguishes proteins primarily associated with CD19, so the complex evidence is not turned into a direct binary contact with every constituent.

Summary: The combined electronic plasma-membrane assignment is well grounded.

Reason: The official signal peptide, transmembrane segment and topology are compatible with plasma-membrane CR2, while direct human surface and complex experiments provide independent support. Current ARBA00027801 branch 227 matches the target; the accompanying subcellular-location mapping is retained. Sequence prediction alone is not presented as a new localization experiment.

Summary: Retain the traceable cell-surface location of the genomic CR2 assignment.

Reason: The available genomic-study abstract identifies the human C3d/EBV receptor but does not report a new localization assay. Its NAS plasma-membrane assertion is independently supported by human receptor-complex experiments. Full original access was not recovered, and the citation is not recharacterized as a direct imaging experiment.

Summary: The complement-fragment binding reaction explicitly places CR2 at the plasma membrane.

Reason: The actual Reactome input entity 197936 is human P20023 residues 21–1033 in GO:0005886, and the reaction output contains that same entity in the CR2–C3-fragment complex. This is an authenticated curator pathway location, consistent with experimental surface-receptor evidence. It is not a new all-isoform localization measurement.

Summary: The co-receptor assembly reaction explicitly retains plasma-membrane CR2.

Reason: The Reactome input/output component path reaches the same human P20023 entity through CR2:C3d,C3dg,iC3b and its complex with CD19:CD81. Its structured compartment is GO:0005886. This row represents complex assembly context, distinct from the preceding ligand-binding reaction; neither event creates a new primary localization experiment.

Summary: Specify B-cell activation within the broad immune-response assertion.

Reason: The historical cloning paper identifies the receptor rather than experimentally measuring all immune outcomes. Independent complement-ligand binding and B-cell receptor co-engagement show how CR2 itself performs immune recognition and signal amplification. Refine this target-level assertion to B-cell activation rather than treating broad immune response as evidence for every T-cell or complement-inhibitory process. This target-level refinement intentionally converges on the separately retained GO:0042113 IDA assertion; it does not create an additional NEW annotation.

Proposed replacements: B cell activation

Summary: Retain the electronic alternative-pathway role as a contextual complement effect.

Reason: Current ARBA00086627 branch 0 matches the target. The human B-cell literature describes CR2-mediated C3-fragment deposition and distinguishes alternative-pathway conditions from assays where all pathways operate. This supports a contextual complement-amplification role, separate from the receptor-signaling core. It does not make CR2 a complement-cleaving enzyme or resolve the distinct classical-pathway inhibition assertion.

Summary: Retain positive CR2-dependent complement deposition at the human B-cell assay scope.

Reason: The complete abstract explicitly identifies CR2-mediated alternative-pathway activation and compares it with conditions where all pathways are operational. Blocking the CR2 ligand-binding site reduces C3-fragment deposition, while membrane-attack-complex effects depend on assay context. Retain the existing experimental process assertion with curator deference; full Methods were not recovered, and the mixed-pathway experiment alone is not represented as an isolated alternative-pathway assay.

Summary: Specify the plasma membrane within the broad membrane assertion.

Reason: The original human receptor cloning study reports a transmembrane segment and short cytoplasmic tail. Independent human surface and CD19-associated complex experiments establish the plasma-membrane context more precisely. This target-level location refinement does not claim exclusive residence or identical assay coverage of all four products.

Proposed replacements: plasma membrane

Summary: Retain antibody-triggered B-cell differentiation at the reported culture scope.

Reason: The complete abstract reports that selected anti-CR2 antibodies stimulate human B cells and induce polyclonal immunoglobulin secretion after 6–10 days, with T-cell help required. This is positive receptor-triggered differentiation evidence, not developmental expression alone. Retain the experimental curator’s broad B-cell differentiation assignment without claiming a direct lineage-commitment mechanism or generalizing to all CR2 ligands; full Methods were not recovered.

Summary: CR2 directly binds the IgE receptor CD23 in a distinct ligand context.

Reason: Human CD21 SCR1–2 and human CD23 were directly assayed in the full original study. The current term describes binding to an immunoglobulin receptor and fits CD23; its Fc-gamma-RI-specific child does not fit this partner. Distinct IgE and CD21 sites on CD23 do not constitute evidence that CR2 itself binds IgE.

Summary: Retain context-dependent human B-cell proliferation after CR2 engagement.

Reason: Selected anti-CR2 antibodies induce dose-dependent DNA synthesis attributed to B cells in the presence of T-cell help. This positive receptor-engagement response supports the existing proliferation assertion, while full Methods access remains unavailable. It is a downstream culture response rather than a claim that CR2 directly executes cell-cycle machinery or that every CR2 ligand is mitogenic.

Summary: CR2 participates directly in B-cell activation through co-receptor engagement.

Reason: The complete human study abstract describes physical CD21–FCRL5 association and enhanced calcium responses on joint FCRL5/CD21/BCR engagement in cell lines and tonsil B cells. CR2 supplies ligand recognition and co-receptor participation, not merely a downstream expression marker. Retain the existing activation assertion while limiting detailed mechanism to what the available source establishes.

Summary: The human homodimerization assertion needs its exact experimental grounding resolved.

Reason: The available source explicitly studies murine Cr2 glycosylation and uses molecular modeling to relate a variant to receptor dimerization. Its full original Methods were not recovered. The current term requires identical-protein binding to form a homodimer, and the abstract does not resolve the human assay or whether structural packing is the relevant assembly. Preserve the positive experimental curator assertion as unresolved; a mouse-focused title is not evidence of wrong-gene curation.

Summary: CR2 is a component of signaling receptor complexes, with source-specific limits.

Reason: The cited trafficking paper’s actual peptide-array/cargo experiments were read, but its precise CR2 peptide-table linkage was not resolved from the available figure and failed supplement routes. Independent human CR2–CD19 and CD21/FCRL5 complex evidence nevertheless supports the broad component assertion. Retain the original source and distinguish those independent assembly experiments from this trafficking study; do not infer direct contact with every co-complex constituent.

Summary: The classical-complement inhibition transfer remains unresolved at the CR2 target level.

Reason: The actual PTN008569518 GO:0045959 IBD lies on the human target path with no intervening loss. Its literal donors are pig CD46 (O02839), human C4BPA (P04003) and human CR1 (P17927); their complement-regulatory evidence is a legitimate ancestral premise, not proof of the corresponding CR2 mechanism. The GO definition covers any reduction of classical-pathway activation, not only convertase decay. Importantly, PMID:2437238 reports weak factor-I cofactor activity of purified human Raji-cell CR2 for membrane-bound iC3b cleavage, with anti-CR2 inhibition and CR1-contamination controls; the authors explicitly leave physiological relevance unresolved. This does not demonstrate classical-pathway inhibition, but makes a universal absence-of-cofactor argument inaccurate. PMID:31396570 classifies CR2 as non-regulatory in its motif framework; its new functional tests concern CR1 constructs and polydom, not a CR2 loss-of-function assay. In PMID:21452327 soluble CR2 reduced autoimmune/complement-deposition measures in MRL/lpr mice, but the authors identify classical-pathway inhibition as an indirect inference and state that C1q deposition is not a pathway-specific assay. These bounded data leave the exact ancestral classical-pathway claim unresolved at the human CR2 target, rather than established or positively contradicted. Retain UNDECIDED for that specific attribution.

Summary: Retain receptor-mediated EBV entry as a real host-exploitation process.

Reason: The complete source abstract reports gp350/220 engagement of the B-cell C3d receptor with adsorption, capping and endocytosis. CR2 supplies the receptor interaction used in entry, so the existing process has positive functional evidence. Full original Methods were not recovered; retain curator deference without expanding to an intrinsic viral replication activity or an all-isoform assay claim.

Summary: The electronic symbiont-entry assignment matches the established EBV receptor role.

Reason: Current ARBA00043454 branch 6 matches the official target, and the independent gp350/220 study supports CR2-mediated viral adsorption and endocytosis. Retain this positive host-exploitation role as non-core. This current rule check is not a historical replay and does not imply entry of every pathogen.

Summary: Retain CD23 binding without reversing the direction of the measured signaling response.

Reason: The recovered original establishes human CD21–CD23 binding. Its functional experiment engages CD21 with soluble CD23 fusion protein or anti-CD21 together with IL-4 and measures IgE output; it does not establish that CR2 activates CD23. GO:0034987 preserves the demonstrated immunoglobulin-receptor interaction without adding the receptor-activity change required by GO:0048018. The original source object and all positive binding evidence remain intact.

Proposed replacements: immunoglobulin receptor binding

Summary: Retain a contextual contribution to type I interferon responses.

Reason: The original 1991 binding/competition and proliferation experiments support an IFN-alpha receptor-associated role; the later human B-cell study additionally reports anti-CR2-sensitive induction of IFN-responsive genes. The exact relationship to IFNAR1/IFNAR2 remains unresolved. The protected GO-CAM names MX1 and EIF2AK2 downstream of CR2 using the 1991 reference, but those named readouts were not measured in that paper. Preserve the original reference and distinguish model interpretation from the actual experiments.

Summary: Retain the exosomal occurrence assertion at its proteomic cargo scope.

Reason: The recovered original main text describes human B-cell exosome purification and mass-spectrometric protein identification. The CR2-specific supplementary peptide table was not recovered, so its exact target peptides and isoform resolution remain unverified. Preserve the experimental curator’s positive cargo assignment, supported contextually by extracellular descendant evidence, without claiming that CR2 performs exosome biogenesis or that all identified proteins belong to one detergent-resistant complex.