id: P49278 gene_symbol: Derp2 product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:6956 label: Dermatophagoides pteronyssinus description: >- Der p 2, a major house dust mite allergen of the NPC2 (ML-domain) family. It is a secreted lipid/sterol-binding protein structurally and functionally homologous to MD-2 (LY96), the LPS-binding component of the TLR4 signalling complex: Der p 2 reconstitutes LPS-driven TLR4 signalling in the absence of MD-2, giving it auto-adjuvant properties that drive allergic sensitization. It is recognized by IgE in most dust-mite-allergic patients, and is the archetype of the "lipid-binding protein as auto-adjuvant" allergen concept that also frames cat Fel d 1. alternative_records: - id: A0ABQ8J715 relationship: REFERENCE_PROTEOME_EQUIVALENT reference_proteome: UP000887458 reviewed_on: '2026-10-19' reason: Retain P49278 as the primary Swiss-Prot accession. The 146-residue reference sequence differs at three residues with full ungapped coverage (97.95% identity), and is strongly separated from other lipid-transfer-family matches. This supports a qualified sequence-based Der p 2 counterpart; its generic transfer-protein label does not independently establish allergenicity or identical immunological properties. evidence: - type: PROTEOME_SEARCH description: MMseqs2 searched 14,675 sequences across UP000887458 at E <= 1e-5 and sensitivity 7.5, returning 6 hits. Every returned sequence was globally aligned using BLOSUM62 with gap-open -10 and extension -0.5. Scores and sequences for all 6 returned candidates are retained, with 6 detailed alignment files. The heuristic search does not establish genomic absence or unique locus identity. supported_by: - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: 'target_sequence_count: 14675' - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: 'candidate_count: 6' - type: SEQUENCE_COMPARISON description: 'A0ABQ8J715: 143 identities across 146 global-alignment columns (97.9452% identity including gaps), 3 substitutions and 0 gap columns. Query coverage is 100.0%; target coverage is 100.0%. Sequence similarity is interpreted in the manual rationale. Identity over paired residues is 97.9452% (143/146); gap columns are excluded from this denominator.' supported_by: - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: |- query_length: 146 target_length: 146 alignment_columns: 146 identities: 143 mismatches: 3 gap_columns: 0 identity_percent: 97.9452 query_coverage_percent: 100.0 target_coverage_percent: 100.0 - type: PROTEOME_MEMBERSHIP description: The primary accession is outside every searched exact-taxon reference proteome. Current UniProt records place A0ABQ8J715 in UP000887458 and give it the same taxon as the primary. supported_by: - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: 'primary_in_any_reference_proteome: false' - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: 'alternative_in_reference_proteome: true' - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: 'same_taxon: true' - type: RECORD_HISTORY description: 'Sampled UniSave observations: 14-OCT-2015, entry version 77.: no Proteomes cross-reference; 07-OCT-2020, entry version 90.: no Proteomes cross-reference; 27-NOV-2024, entry version 102.: UP000515146. These dated observations do not establish uninterrupted membership/absence, the exact change date, or UniProt''s motivation.' supported_by: - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: |- entry_date: 14-OCT-2015, entry version 77. proteomes: [] - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: |- entry_date: 07-OCT-2020, entry version 90. proteomes: [] - reference_id: file:DERPT/Derp2/Derp2-record-evidence.yaml supporting_text: |- entry_date: 27-NOV-2024, entry version 102. proteomes: - UP000515146 existing_annotations: - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Der p 2 is a secreted mite protein; extracellular localization is correct. action: ACCEPT reason: Secreted/excreted mite allergen acting in the extracellular space. supported_by: - reference_id: file:DERPT/Derp2/Derp2-uniprot.txt record_section: ["CC:SIMILARITY"] supporting_text: Belongs to the NPC2 family. - term: id: GO:0015918 label: sterol transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: NPC2/ML-domain proteins bind and transport sterols/lipids; consistent with Der p 2's family and hydrophobic cavity. action: ACCEPT reason: Consistent with the NPC2 lipid/sterol-binding fold. supported_by: - reference_id: file:DERPT/Derp2/Derp2-uniprot.txt record_section: ["CC:SIMILARITY"] supporting_text: Belongs to the NPC2 family. - term: id: GO:0032934 label: sterol binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: The NPC2/ML domain binds sterols/lipids in its hydrophobic cavity; the core molecular function of Der p 2. action: ACCEPT reason: Core lipid/sterol-binding function of the NPC2 family. supported_by: - reference_id: file:DERPT/Derp2/Derp2-uniprot.txt record_section: ["CC:SIMILARITY"] supporting_text: Belongs to the NPC2 family. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19060881 qualifier: enables review: summary: >- Records the direct interaction of Der p 2 with the TLR4 receptor complex (MD-2 functional mimicry). The bare "protein binding" term is uninformative on its own; the meaningful activity is the TLR4-signalling enhancement captured as a NEW process annotation below. action: KEEP_AS_NON_CORE reason: Uninformative parent term; the specific functional consequence (TLR4 signalling) is annotated separately. supported_by: - reference_id: PMID:19060881 supporting_text: facilitating signalling through direct interactions with the TLR4 complex, and - term: id: GO:0034145 label: positive regulation of toll-like receptor 4 signaling pathway evidence_type: IDA original_reference_id: PMID:19060881 qualifier: involved_in review: summary: >- NEW (proposed). Der p 2 functionally mimics MD-2, reconstituting LPS-driven TLR4 signalling in the absence of MD-2 and thereby enhancing innate immune activation (auto-adjuvant). Directly parallels the LPS/TLR4 activity annotated for cat Fel d 1. action: NEW reason: Trompette et al. 2009 experimentally demonstrated Der p 2 reconstitutes/enhances TLR4 signalling via MD-2 mimicry. supported_by: - reference_id: PMID:19060881 supporting_text: reconstituting LPS-driven TLR4 signalling in the absence of MD-2. - term: id: GO:0001530 label: lipopolysaccharide binding evidence_type: IDA original_reference_id: PMID:19060881 qualifier: enables review: summary: >- NEW (proposed). Der p 2 is a functional homolog of MD-2 (LY96), the LPS-binding component of the TLR4 complex, and reconstitutes LPS-driven TLR4 signalling in the absence of MD-2 — substituting for MD-2's LPS-presenting role, which implies LPS (lipid A) binding by its ML-domain cavity. This is the molecular basis of its auto-adjuvant activity and directly parallels the LPS binding annotated for cat Fel d 1. action: NEW reason: >- Der p 2 functionally substitutes for MD-2 (the LPS-binding TLR4 co-receptor), reconstituting LPS-driven TLR4 signalling; LPS/lipid-A binding by its ML domain is the mechanistic basis and a more specific MF than generic sterol binding for its immunomodulatory role. supported_by: - reference_id: PMID:19060881 supporting_text: reconstituting LPS-driven TLR4 signalling in the absence of MD-2. core_functions: - description: >- Secreted NPC2/ML-domain lipid (sterol) binding protein that binds and transports sterols/lipids in its hydrophobic cavity. molecular_function: id: GO:0032934 label: sterol binding directly_involved_in: - id: GO:0015918 label: sterol transport supported_by: - reference_id: file:DERPT/Derp2/Derp2-uniprot.txt record_section: ["CC:SIMILARITY"] supporting_text: Belongs to the NPC2 family. locations: - id: GO:0005576 label: extracellular region - description: >- Immunomodulatory MD-2 mimic: Der p 2 binds LPS (lipid A) via its ML-domain cavity and engages the TLR4 complex, reconstituting/enhancing LPS-driven TLR4 signalling even without MD-2 and functioning as an auto-adjuvant that promotes allergic sensitization. (The same ML-domain hydrophobic cavity underlies its sterol/lipid binding above; LPS binding is the activity directly relevant to TLR4 engagement.) molecular_function: id: GO:0001530 label: lipopolysaccharide binding directly_involved_in: - id: GO:0034145 label: positive regulation of toll-like receptor 4 signaling pathway supported_by: - reference_id: PMID:19060881 supporting_text: reconstituting LPS-driven TLR4 signalling in the absence of MD-2. locations: - id: GO:0005576 label: extracellular region proposed_new_terms: [] suggested_questions: - question: What endogenous lipid does Der p 2 carry, and is lipid cargo required for its TLR4 auto-adjuvant activity (as for MD-2)? experts: [] suggested_experiments: - hypothesis: Der p 2's lipid-binding cavity is required for its TLR4-reconstituting auto-adjuvant activity. description: Compare wild-type and cavity-mutant Der p 2 for LPS binding and TLR4 reporter activation in MD-2-deficient cells. experiment_type: structure-function / signalling assay references: - id: file:DERPT/Derp2/Derp2-record-evidence.yaml title: Compact archived record and sequence evidence for P49278 - 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:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:19060881 title: Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. findings: - statement: Der p 2 has structural and functional homology with MD-2 and reconstitutes LPS-driven TLR4 signalling in the absence of MD-2, acting as an auto-adjuvant. supporting_text: reconstituting LPS-driven TLR4 signalling in the absence of MD-2. reference_review: relevance: HIGH correctness: VERIFIED review_notes: PMC full text; primary evidence for Der p 2 MD-2 mimicry and TLR4-signalling enhancement (auto-adjuvant), the Der p 2 / Fel d 1 parallel. - id: file:DERPT/Derp2/Derp2-uniprot.txt title: UniProt entry P49278 (Mite group 2 allergen Der p 2), Dermatophagoides pteronyssinus findings: - statement: Der p 2 belongs to the NPC2 (ML-domain) lipid/sterol-binding family; major house dust mite allergen. record_section: ["CC:SIMILARITY"] supporting_text: Belongs to the NPC2 family. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Curated UniProt record; source for the NPC2 sterol/lipid-binding family classification.