id: Q92521
gene_symbol: PIGB
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGB (GPI alpha-1,2-mannosyltransferase 3; also called GPI mannosyltransferase
  III, GPI-MT-III) is a multi-pass endoplasmic reticulum membrane protein that acts
  in glycosylphosphatidylinositol (GPI) anchor biosynthesis. It is a dolichyl-phosphate-mannose
  (Dol-P-Man)-dependent alpha-1,2-mannosyltransferase that transfers the third mannose,
  via an alpha-1,2 linkage, onto the growing GPI intermediate (Man2 to Man3) in the
  ER lumen. This third mannose is the residue that subsequently receives the bridging
  ethanolamine-phosphate (added by PIGO) to which the mature protein is ultimately
  attached, so PIGB activity is required for building a functional protein-anchoring
  GPI. The catalytic domain faces the ER lumen. Biallelic loss-of-function variants
  cause an inherited GPI-deficiency presenting as developmental and epileptic encephalopathy
  (DEE80), with refractory seizures, developmental delay/intellectual disability, and
  variable axonal neuropathy.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- 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: PMID:8861954
  title: PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal
    domain, is involved in transferring the third mannose of the GPI anchor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original cloning and functional characterization of human PIG-B;
      establishes ER transmembrane topology with a large lumenal (catalytic) domain
      and its role in transferring the third mannose of the GPI anchor. Cached record
      is abstract-only (full_text_available false), but the abstract directly supports
      the MF, BP, and CC annotations attributed to it.
- id: Reactome:R-HSA-162710
  title: Synthesis of glycosylphosphatidylinositol (GPI)
  findings: []
- id: Reactome:R-HSA-162821
  title: mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + dolichol
    phosphate D-mannose -> mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4)
    glucosaminyl-acyl-PI + dolichol phosphate
  findings: []
- id: file:human/PIGB/PIGB-uniprot.txt
  title: UniProtKB entry Q92521 (PIGB_HUMAN)
  findings: []
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: PIGB is a multi-pass ER membrane protein and acts in the ER; the phylogenetic
      (IBA) is_active_in assertion of ER-membrane localization is correct and represents
      the core site of action.
    action: ACCEPT
    reason: Consistent with experimental localization of human PIG-B to the ER membrane
      and with UniProt subcellular location. This is the compartment where GPI-anchor
      mannosylation occurs.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: ER transmembrane protein with an amino-terminal portion of
        approximately 60
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0000026
    label: alpha-1,2-mannosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: PIGB is a Dol-P-Man-dependent alpha-1,2-mannosyltransferase; this IBA
      term correctly captures the alpha-1,2-mannosyltransferase molecular function
      at a general level. A more specific term (GO:0120564) is also present for the
      exact reaction.
    action: ACCEPT
    reason: The alpha-1,2-mannosyltransferase activity is well supported experimentally
      and by the enzyme's Rhea catalytic activity. It is a correct, if less specific,
      parent of the characterized reaction; retained as a correct MF.
    supported_by:
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Alpha-1,2-mannosyltransferase that catalyzes the transfer of
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: the third mannose, via an alpha-1,2 bond, from a dolichol-phosphate-
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PIGB catalyzes an essential mannosylation step in GPI-anchor biosynthesis;
      the phylogenetic involved_in assertion for GPI anchor biosynthetic process is
      correct and represents the core biological process.
    action: ACCEPT
    reason: Directly supported by experimental characterization (transfer of the third
      mannose of the GPI anchor) and by the UniProt pathway assignment to glycosylphosphatidylinositol-anchor
      biosynthesis.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: is involved in transferring the third mannose of the GPI anchor
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic mapping from the UniProtKB/Swiss-Prot subcellular-location
      vocabulary to ER membrane; matches the experimentally determined location.
    action: ACCEPT
    reason: The UniProt SubCell mapping to endoplasmic reticulum membrane is consistent
      with the experimental IDA localization and with the protein's multi-pass ER
      topology.
    supported_by:
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0016757
    label: glycosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-to-GO mapping (IPR005599, GPI mannosyltransferase) to the generic
      glycosyltransferase activity root term. Correct but uninformative relative to
      the specific mannosyltransferase terms already annotated.
    action: ACCEPT
    reason: PIGB is a member of glycosyltransferase family 22 (GT22) and is a genuine
      glycosyltransferase, so the IEA mapping is not wrong; it is simply a broad parent
      of the more specific alpha-1,2-mannosyltransferase / GPI mannosyltransferase
      terms. Retained as a correct high-level MF (the specific terms carry the core
      function).
    supported_by:
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Belongs to the glycosyltransferase 22 family. PIGB
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162710
  qualifier: involved_in
  review:
    summary: Reactome-traceable assertion that PIGB participates in GPI (glycosylphosphatidylinositol)
      synthesis; correct core biological process.
    action: ACCEPT
    reason: The Reactome pathway 'Synthesis of glycosylphosphatidylinositol (GPI)'
      places PIGB in the GPI-anchor biosynthetic process, in agreement with the experimental
      and phylogenetic BP annotations.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: is involved in transferring the third mannose of the GPI anchor
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway (UPA00196) vocabulary mapping to GPI-anchor biosynthetic process;
      consistent with the UniProt pathway annotation.
    action: ACCEPT
    reason: The UniPathway mapping to glycosylphosphatidylinositol-anchor biosynthesis
      is correct and corroborates the core biological process from multiple independent
      evidence lines.
    supported_by:
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
- term:
    id: GO:0004376
    label: GPI mannosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162821
  qualifier: enables
  review:
    summary: Reactome-traceable assertion (the reaction adding the third mannose of
      the GPI anchor) that PIGB has GPI mannosyltransferase activity; a correct family-level
      molecular-function term for this enzyme.
    action: ACCEPT
    reason: The Reactome reaction catalyzed by PIG-B (addition of the third mannose)
      corresponds to GPI mannosyltransferase activity. This is a correct MF, more
      specific than the glycosyltransferase root and consistent with the specific
      IDA term GO:0120564.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: is involved in transferring the third mannose of the GPI anchor
- term:
    id: GO:0120564
    label: dol-P-Man:Man(2)GlcN-acyl-PI alpha-1,2-mannosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:8861954
  qualifier: enables
  review:
    summary: Experimentally supported (IDA) specific molecular function - the Dol-P-Man-dependent
      alpha-1,2-mannosyltransferase that adds the third mannose to the Man2 GPI intermediate.
      This is the most precise MF term for PIGB and its core catalytic activity.
    action: ACCEPT
    reason: Directly matches the characterized reaction of human PIG-B (transfer of
      the third mannose, via an alpha-1,2 bond, from dolichol-phosphate-mannose to
      the GPI intermediate) and the corresponding UniProt catalytic activity (Rhea:RHEA:61004).
      This is the enzyme's defining function.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: is involved in transferring the third mannose of the GPI anchor
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: the third mannose, via an alpha-1,2 bond, from a dolichol-phosphate-
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162821
  qualifier: located_in
  review:
    summary: Reactome-traceable assertion of ER-membrane localization; consistent
      with the experimentally determined location.
    action: ACCEPT
    reason: GPI-anchor mannosylation occurs at the ER membrane; the Reactome location
      matches the IDA and IBA ER-membrane annotations and UniProt subcellular location.
    supported_by:
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:8861954
  qualifier: located_in
  review:
    summary: Experimentally determined (IDA) ER-membrane localization; PIG-B is an
      ER transmembrane protein with its catalytic (lumenal) domain in the ER lumen.
      This is the core cellular location.
    action: ACCEPT
    reason: Takahashi et al. showed PIG-B is an ER transmembrane protein whose functional
      site resides on the lumenal side of the ER membrane, directly supporting ER
      membrane localization.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: ER transmembrane protein with an amino-terminal portion of
        approximately 60
    - reference_id: PMID:8861954
      supporting_text: lumenal side of the ER membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8861954
  qualifier: involved_in
  review:
    summary: Experimentally supported (IDA) involvement in GPI-anchor biosynthesis
      - PIG-B was identified as the complementation-class-B gene required for transferring
      the third mannose of the GPI anchor. Core biological process.
    action: ACCEPT
    reason: The defining experimental finding of Takahashi et al. 1996 is that PIG-B
      is required for GPI-anchor biosynthesis (transfer of the third mannose), directly
      supporting this BP annotation.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: is involved in transferring the third mannose of the GPI anchor
    - reference_id: PMID:8861954
      supporting_text: The GPI anchor precursor is synthesized in the endoplasmic
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:8861954
  qualifier: located_in
  review:
    summary: Generic 'membrane' localization asserted (NAS) from the 1996 paper. Not
      wrong, but it is an uninformative parent of the specific ER-membrane annotations
      already present.
    action: MARK_AS_OVER_ANNOTATED
    reason: PIGB is a multi-pass ER membrane protein, so 'membrane' is technically
      correct but redundant and less informative than the endoplasmic reticulum membrane
      (GO:0005789) annotations supported by the same and other evidence. Marked as
      over-annotated rather than removed because the NAS assertion is not incorrect.
    supported_by:
    - reference_id: PMID:8861954
      supporting_text: ER transmembrane protein with an amino-terminal portion of
        approximately 60
    - reference_id: file:human/PIGB/PIGB-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
core_functions:
- description: Dolichyl-phosphate-mannose (Dol-P-Man)-dependent alpha-1,2-mannosyltransferase
    (GPI mannosyltransferase III) that transfers the third mannose onto the GPI intermediate
    (Man2 to Man3) during GPI-anchor biosynthesis in the ER lumen.
  molecular_function:
    id: GO:0120564
    label: dol-P-Man:Man(2)GlcN-acyl-PI alpha-1,2-mannosyltransferase activity
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:8861954
    supporting_text: is involved in transferring the third mannose of the GPI anchor
  - reference_id: file:human/PIGB/PIGB-uniprot.txt
    supporting_text: the third mannose, via an alpha-1,2 bond, from a dolichol-phosphate-