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.
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
      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
      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
      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
    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: 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.
    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.