id: Q2TAA5
gene_symbol: ALG11
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ALG11 is an endoplasmic reticulum membrane alpha-1,2-mannosyltransferase
  (EC 2.4.1.131) of the dolichol-linked oligosaccharide (LLO) assembly pathway. Using
  GDP-mannose as donor, it adds the fourth and fifth mannose residues onto Man3GlcNAc2-PP-dolichol
  to produce Man5GlcNAc2-PP-dolichol, the final cytoplasmic-face LLO intermediate;
  this glycan is then flipped into the ER lumen (by RFT1) for continued assembly and
  eventual transfer to nascent proteins during protein N-linked glycosylation. It
  is a single-pass ER membrane protein whose catalytic domain faces the cytosol and
  belongs to the glycosyltransferase group 1 family (GT4 subfamily). Loss of function
  causes ALG11-CDG (congenital disorder of glycosylation type Ip), a multisystem disorder
  with under-glycosylated serum glycoproteins.
existing_annotations:
- term:
    id: GO:0004377
    label: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred core molecular function. This is the exact
      biochemical activity ALG11 catalyzes and is directly supported by experimental
      characterization in human cells.
    action: ACCEPT
    reason: Core molecular function of ALG11. The IBA is concordant with the human
      IDA (PMID:20080937) and with the UniProt-curated catalytic activity (EC 2.4.1.131).
    supported_by:
    - reference_id: PMID:20080937
      supporting_text: caused by the deficiency of
        GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase, encoded by the
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: "Catalyzes, on\nCC       the cytoplasmic face of the endoplasmic\
        \ reticulum, the addition of the\nCC       fourth and fifth mannose residues"
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred participation in dolichol-linked oligosaccharide
      (LLO) biosynthesis, the pathway in which ALG11 adds the fourth and fifth mannoses
      to Man3GlcNAc2-PP-dolichol.
    action: ACCEPT
    reason: Core biological process. Concordant with the human IMP (PMID:20080937),
      where patient fibroblasts accumulate the LLO intermediates upstream of the ALG11
      step.
    supported_by:
    - reference_id: PMID:20080937
      supporting_text: accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred site of action at the ER membrane, where LLO
      assembly occurs on the cytoplasmic face.
    action: ACCEPT
    reason: Core cellular component. Concordant with UniProt subcellular location
      and the human IDA localization study (PMID:20080937).
    supported_by:
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0004377
    label: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated electronic inference of the same core catalytic activity from
      InterPro, RHEA:29523 and EC:2.4.1.131 mappings.
    action: ACCEPT
    reason: Correct and specific. The RHEA/EC mapping matches the experimentally verified
      reaction, and this is the core molecular function.
    supported_by:
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: EC=2.4.1.131 {ECO:0000269|PubMed:20080937}
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated electronic inference of ER membrane localization from the UniProt
      Subcellular Location keyword mapping.
    action: ACCEPT
    reason: Correct core localization, consistent with curated UniProt location and
      experimental IDA.
    supported_by:
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016757
    label: glycosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro (IPR001296, Glyco_trans_1) domain-based inference of a general
      glycosyltransferase activity.
    action: ACCEPT
    reason: Correct but a broad parent of the specific mannosyltransferase activity
      (GO:0004377). Acceptable as a domain-level IEA that is legitimately more general
      than the experimentally supported term; not misleading.
    supported_by:
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: Belongs to the glycosyltransferase group 1 family
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Single high-throughput affinity-purification mass spectrometry (BioPlex)
      interaction with GLA (alpha-galactosidase A, P06280). Bare "protein binding"
      is uninformative about ALG11's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The IPI derives from a proteome-scale AP-MS screen and captures a physical
      co-purification rather than a characterized functional interaction; the term
      "protein binding" adds no information about ALG11's actual mannosyltransferase
      function. Retained (not removed) per curation policy for experimental IPIs, but
      flagged as over-annotation.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: "affinity purification \nof 10,128 human proteins-half the proteome-in\
        \ 293T cells"
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:20080937
  qualifier: involved_in
  review:
    summary: Human mutant-phenotype evidence (patient with p.L86S) for a role in LLO
      biosynthesis; patient fibroblasts accumulate Man3GlcNAc2-PP-dolichol/Man4GlcNAc2-PP-dolichol
      and are deficient in elongating Man3GlcNAc2-PP-dolichol.
    action: ACCEPT
    reason: Directly supported core biological process; the phenotype pinpoints the
      ALG11 step in LLO assembly, and complementation with WT hALG11 rescued it.
    supported_by:
    - reference_id: PMID:20080937
      supporting_text: deficient in elongating Man3GlcNAc2-PP-dolichol
- term:
    id: GO:0004377
    label: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:20080937
  qualifier: enables
  review:
    summary: Direct assay of ALG11 mannosyltransferase activity in human fibroblasts;
      the CDG1P p.L86S variant decreases this activity, establishing the catalytic
      function experimentally.
    action: ACCEPT
    reason: Core molecular function with direct experimental support. This is the
      exact GOA molecular-function term used in core_functions.
    supported_by:
    - reference_id: PMID:20080937
      supporting_text: caused by the deficiency of
        GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase, encoded by the
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: EC=2.4.1.131 {ECO:0000269|PubMed:20080937}
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:20080937
  qualifier: is_active_in
  review:
    summary: Immunofluorescence localization of ALG11 to the ER in control and patient
      fibroblasts; the p.L86S variant does not mislocalize the protein.
    action: ACCEPT
    reason: Directly supported core cellular component. The localization study confirms
      ER membrane residence and shows the disease variant retains normal localization.
    supported_by:
    - reference_id: PMID:20080937
      supporting_text: indicating no mislocalization or
    - reference_id: file:human/ALG11/ALG11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006487
    label: protein N-linked glycosylation
  evidence_type: IMP
  original_reference_id: PMID:20080937
  qualifier: involved_in
  review:
    summary: Human mutant-phenotype evidence for a role in protein N-linked glycosylation;
      the patient shows partial loss of complete N-glycan side chains (serum transferrin
      hypoglycosylation, a CDG-I signature).
    action: ACCEPT
    reason: Core biological process. ALG11 builds the LLO precursor that is ultimately
      transferred to asparagine residues; its deficiency causes the underglycosylation
      phenotype diagnostic of CDG-I.
    supported_by:
    - reference_id: PMID:20080937
      supporting_text: the partial loss of complete N-glycan
- term:
    id: GO:0000026
    label: alpha-1,2-mannosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4551297
  qualifier: enables
  review:
    summary: Reactome author-statement annotation to the general alpha-1,2-mannosyltransferase
      activity, the parent of the specific ALG11 activity term.
    action: ACCEPT
    reason: Correct but a less-specific parent of GO:0004377. Retained as an accurate
      (if more general) molecular-function annotation from a reliable TAS source.
    supported_by:
    - reference_id: Reactome:R-HSA-4551297
      supporting_text: transfers the fourth and fifth mannoses (Man) to the N-glycan
        precursor in an alpha-1,2 orientation
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4551297
  qualifier: located_in
  review:
    summary: Reactome author-statement localization of ALG11 to the ER membrane, where
      it acts on the cytosolic face during LLO assembly.
    action: ACCEPT
    reason: Correct core cellular component, concordant with the IDA and IBA evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-4551297
      supporting_text: These additions are the last two on the cytosolic side of the
        ER membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput mass-spectrometry detection of ALG11 in a membrane-proteome
      survey of the YTS NK-like cell line. Generic "membrane" localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: A proteome-scale membrane-fraction survey (ALG11 was not the study subject)
      supporting only the very general term "membrane", which is subsumed by the specific
      and well-supported "endoplasmic reticulum membrane". Retained but flagged as
      over-annotation.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: identified 1843 proteins with high confidence
core_functions:
- description: Alpha-1,2-mannosyltransferase that adds the fourth and fifth mannose
    residues from GDP-mannose onto Man3GlcNAc2-PP-dolichol, producing Man5GlcNAc2-PP-dolichol
    on the cytoplasmic face of the ER membrane, as part of dolichol-linked oligosaccharide
    assembly for protein N-linked glycosylation.
  molecular_function:
    id: GO:0004377
    label: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
  directly_involved_in:
  - id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:20080937
    supporting_text: caused by the deficiency of
      GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase, encoded by the
  - reference_id: file:human/ALG11/ALG11-uniprot.txt
    supporting_text: "Catalyzes, on\nCC       the cytoplasmic face of the endoplasmic\
      \ reticulum, the addition of the\nCC       fourth and fifth mannose residues"
- description: Through building the Man5GlcNAc2-PP-dolichol LLO intermediate, ALG11
    contributes to protein N-linked glycosylation; its deficiency causes hypoglycosylation
    of serum glycoproteins (ALG11-CDG / CDG type Ip).
  molecular_function:
    id: GO:0004377
    label: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
  directly_involved_in:
  - id: GO:0006487
    label: protein N-linked glycosylation
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:20080937
    supporting_text: the partial loss of complete N-glycan
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: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:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane-proteome MS survey of YTS NK-like cells;
      ALG11 detected in the membrane fraction. Correctly cited for a generic HDA membrane
      annotation but contributes no functional insight and is subsumed by the specific
      ER membrane annotations.
- id: PMID:20080937
  title: A severe human metabolic disease caused by deficiency of the endoplasmatic
    mannosyltransferase hALG11 leads to congenital disorder of glycosylation-Ip.
  findings:
  - statement: Deficiency of human ALG11 (GDP-Man:Man3GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase)
      causes CDG-Ip; patient fibroblasts accumulate Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol
      and are deficient in elongating Man3GlcNAc2-PP-dolichol.
    supporting_text: accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol
  - statement: The homozygous p.L86S variant reduces enzyme activity without altering
      ER localization; causality confirmed by rescue with WT hALG11 and yeast alg11-delta
      complementation.
    supporting_text: indicating no mislocalization or
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary paper establishing ALG11 catalytic activity, LLO-pathway
      role, ER localization and disease (CDG-Ip). Cache is abstract-only but the abstract
      directly supports the MF, BP and CC annotations; PubMed-verified.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale AP-MS interactome study; source of the ALG11
      IPI to GLA (P06280). Correctly cited but the interaction is a high-throughput
      co-purification supporting only bare "protein binding".
- id: Reactome:R-HSA-4551297
  title: Defective ALG11 does not transfer Man to the N-glycan precursor
  findings:
  - statement: ALG11 transfers the fourth and fifth mannoses to the N-glycan precursor
      in an alpha-1,2 orientation, the last two additions on the cytosolic side of
      the ER membrane before the glycan is flipped to the ER lumen.
    supporting_text: transfers the fourth and fifth mannoses (Man) to the N-glycan
      precursor in an alpha-1,2 orientation
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction describing the ALG11 step and its loss-of-function
      disease (CDG-1p). Title left exactly as fetched.