id: O75352
gene_symbol: MPDU1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MPDU1 (Lec35; suppressor of Lec15 and Lec35 glycosylation mutation homolog, SL15) is a
  polytopic endoplasmic reticulum membrane protein of the MPDU1/PQ-loop family that is
  required for efficient utilization of the lipid-linked monosaccharide donors
  dolichyl-phosphate-mannose (Dol-P-Man) and dolichyl-phosphate-glucose (Dol-P-Glc) on
  the lumenal side of the ER. It is not itself a glycosyltransferase and has no known
  catalytic activity; rather it acts as a utilization/presentation factor that makes the
  mannosyl and glucosyl groups of these donors available to the lumenal
  glycosyltransferases, controlling an aspect of donor orientation in the ER membrane.
  Through this role it supports mannosylation and glucosylation steps of dolichol-linked
  oligosaccharide (lipid-linked oligosaccharide, LLO) assembly in protein N-glycosylation,
  as well as GPI-anchor biosynthesis and protein O- and C-mannosylation. Loss of function
  causes MPDU1-CDG (congenital disorder of glycosylation type If), a multisystem disorder
  featuring under-glycosylation of serum glycoproteins with skin (ichthyosis),
  neurological and visual involvement.
alternative_products:
- name: '1'
  id: O75352-1
- name: '2'
  id: O75352-2
  sequence_note: VSP_056349, VSP_056350
existing_annotations:
- term:
    id: GO:0009312
    label: oligosaccharide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      PAN-GO phylogenetic (IBA) annotation to the general parent term for oligosaccharide
      biosynthesis. This is consistent with MPDU1's established role in dolichol-linked
      oligosaccharide (LLO) assembly; it is broader than the experimentally supported child
      term GO:0006488 (dolichol-linked oligosaccharide biosynthetic process), but a
      correct, conservative phylogenetic call.
    action: ACCEPT
    reason: >-
      The IBA call is correct at the family level and has been through phylogenetic review.
      It is retained at its (general) level; the more specific process the experimental
      evidence supports is captured by the separate GO:0006488 annotation. Kept as a
      conservative phylogenetic annotation rather than second-guessed.
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: >-
        The Lec35 gene product (Lec35p) is required for utilization of the mannose donor
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic mapping from the UniProt subcellular-location vocabulary to the generic
      term "membrane". MPDU1 is indeed a multi-pass membrane protein, but its specific
      residence is the ER membrane (GO:0005789).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong, but "membrane" is an uninformative parent superseded by the more specific
      and evidenced GO:0005789 (endoplasmic reticulum membrane). Retained as an
      over-annotated generic location.
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: predicts a novel endoplasmic reticulum membrane protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Binary interaction with MANBAL (Q9NQG1) reported in the HuRI human interactome map.
      This interaction is independently recorded in the UniProt entry (O75352; Q9NQG1:
      MANBAL; NbExp=3). However, the annotated term is the uninformative generic
      "protein binding".
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "protein binding" (GO:0005515) is too generic to convey MPDU1's molecular role, per
      curation guidelines. The interaction with MANBAL is genuine and physiologically
      plausible (a small ER-membrane protein of unclear function), but this bare-binding
      term does not describe MPDU1's function; the underlying experimental IPI is retained
      rather than removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
    - reference_id: file:human/MPDU1/MPDU1-uniprot.txt
      supporting_text: 'O75352; Q9NQG1: MANBAL'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence-based localization to mitochondrion. This conflicts with the
      well-established ER-membrane residence of MPDU1 (a Dol-P-Man/Dol-P-Glc utilization
      factor of ER-lumenal glycosylation) and with its MPDU1/PQ-loop family membership;
      no functional evidence supports a mitochondrial role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Likely reflects immunofluorescence cross-reactivity or partial signal rather than a
      genuine mitochondrial function. Because this is an experimental (IDA) HPA annotation
      whose primary images were not reviewed, it is flagged as over-annotated rather than
      removed; the ER membrane is the functionally relevant location.
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: predicts a novel endoplasmic reticulum membrane protein
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence localization to the endoplasmic reticulum, consistent with
      the established biology of MPDU1/Lec35 as an ER protein required for utilization of
      dolichol-phosphate sugar donors in ER-lumenal glycosylation.
    action: ACCEPT
    reason: >-
      Correct localization. Slightly broader than the specific ER-membrane term but
      accurate and independently supported; retained.
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: predicts a novel endoplasmic reticulum membrane protein
- term:
    id: GO:0009312
    label: oligosaccharide biosynthetic process
  evidence_type: IGI
  original_reference_id: PMID:11733564
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction evidence from the CDG-If study: MPDU1 mutations cause
      accumulation of incomplete lipid-linked oligosaccharide precursors, and expression
      of normal Lec35 cDNA restores normal LLO biosynthesis. The essence is correct but
      the term is the general parent.
    action: MODIFY
    reason: >-
      The supporting genetics specifically concern dolichol-linked (lipid-linked)
      oligosaccharide biosynthesis, so the more specific child term GO:0006488 is the
      appropriate annotation.
    proposed_replacement_terms:
    - id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    supported_by:
    - reference_id: PMID:11733564
      supporting_text: >-
        Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of
        patients restored normal lipid-linked oligosaccharide biosynthesis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16237761
  qualifier: enables
  review:
    summary: >-
      IPI derived from a yeast two-hybrid screen of a liver cDNA library for proteins
      binding the hepatitis C virus F (ARFP) protein (bait UniProtKB:P0C045). MPDU1 was
      captured as a prey. The annotated term is the uninformative generic "protein
      binding" and the interaction is with a viral protein of uncertain relevance to
      MPDU1's cellular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" (GO:0005515) does not describe MPDU1's molecular function,
      and a single Y2H hit against a viral bait is weak, non-core evidence. Per curation
      policy the underlying experimental IPI is not removed but is flagged as an
      uninformative over-annotation.
    supported_by:
    - reference_id: PMID:16237761
      supporting_text: >-
        yeast two-hybrid system is an effective method for identifying hepatocyte proteins
        interacting with F protein of hepatitis C virus
- 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 MPDU1 in the membrane proteome of an
      NK-like cell line. Confirms MPDU1 is a membrane protein but only to the generic
      "membrane" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Consistent with MPDU1 being an integral membrane protein, but "membrane" is generic
      and superseded by the specific ER membrane location (GO:0005789). A proteome-scale MS
      membrane-preparation hit does not localize the protein to a specific compartment.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        approximately 40% of the identified proteins were predicted as plausible membrane
        proteins
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:11179430
  qualifier: located_in
  review:
    summary: >-
      MPDU1/Lec35 is an ER membrane protein; the founding functional paper predicts a
      novel ER membrane protein and localizes its activity (controlling Dol-P-Man
      orientation) to the ER membrane. This is the specific, functionally relevant
      location.
    action: ACCEPT
    reason: >-
      Correct and specific core location, corroborated by HPA IDA (ER) and by the
      multi-pass membrane topology. This is the preferred CC term over generic "membrane".
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: predicts a novel endoplasmic reticulum membrane protein
    - reference_id: PMID:11179430
      supporting_text: >-
        Lec35p controls an aspect of MPD orientation in the endoplasmic reticulum membrane
        that is crucial for its activity as a donor substrate
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:11179430
  qualifier: involved_in
  review:
    summary: >-
      Annotation reflecting that MPDU1-supported N-glycosylation is important for
      downstream glycoprotein folding (the source paper notes that LLOs are important for
      protein folding). This is a downstream consequence, not MPDU1's molecular role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      MPDU1 does not act in the protein-folding machinery; it enables use of dolichol-P
      sugar donors for glycan assembly, and correct N-glycosylation in turn supports
      glycoprotein folding. Annotating MPDU1 directly to protein folding over-attributes a
      distal, indirect effect and is better captured by its glycosylation-biosynthesis
      annotations.
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: important for functions such as protein folding and membrane anchoring
- term:
    id: GO:0006488
    label: dolichol-linked oligosaccharide biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:11733564
  qualifier: involved_in
  review:
    summary: >-
      Core biological process: MPDU1/Lec35 is required for utilization of
      dolichylphosphomannose and dolichylphosphoglucose in assembly of the dolichol-linked
      (lipid-linked) oligosaccharide precursor for N-glycosylation; CDG-If patients
      accumulate incomplete LLO precursors and normal LLO biosynthesis is restored by
      Lec35 cDNA.
    action: ACCEPT
    reason: >-
      Directly supported and represents the specific, core biological process of MPDU1.
    supported_by:
    - reference_id: PMID:11733564
      supporting_text: >-
        accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein
        glycosylation
    - reference_id: PMID:11179430
      supporting_text: >-
        glucose-P-dolichol (GPD)-dependent glucosylation of LLO. Both were found to require
        Lec35p
- term:
    id: GO:0009312
    label: oligosaccharide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11179430
  qualifier: involved_in
  review:
    summary: >-
      IDA to the general parent term based on the demonstration that Lec35p is required
      for utilization of the mannose donor (MPD) in synthesis of lipid-linked
      oligosaccharides. Correct in essence but too general.
    action: MODIFY
    reason: >-
      The experimental evidence concerns dolichol-linked (lipid-linked) oligosaccharide
      assembly specifically, so the more precise child term GO:0006488 should be used.
    proposed_replacement_terms:
    - id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    supported_by:
    - reference_id: PMID:11179430
      supporting_text: >-
        The Lec35 gene product (Lec35p) is required for utilization of the mannose donor
core_functions:
- description: >-
    Utilization/presentation of dolichyl-phosphate-mannose (Dol-P-Man) and
    dolichyl-phosphate-glucose (Dol-P-Glc) on the lumenal side of the ER membrane, enabling
    the mannosylation and glucosylation steps of dolichol-linked (lipid-linked)
    oligosaccharide assembly for protein N-glycosylation (and, via the same donor pathways,
    GPI-anchor and O-/C-mannosylation). MPDU1 has no known catalytic activity and is not
    itself a glycosyltransferase; it controls donor orientation/availability in the ER
    membrane.
  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:11179430
    supporting_text: >-
      The Lec35 gene product (Lec35p) is required for utilization of the mannose donor
  - reference_id: PMID:11179430
    supporting_text: >-
      Lec35p is not directly required for the enzymatic transfer of mannose from the donor
      to the acceptor substrate
  - reference_id: PMID:11733564
    supporting_text: >-
      accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein
      glycosylation
  - reference_id: file:human/MPDU1/MPDU1-uniprot.txt
    supporting_text: Required for normal utilization of mannose-dolichol phosphate
  knowledge_gaps:
  - gap_statement: >-
      The precise molecular mechanism by which MPDU1 promotes utilization of Dol-P-Man and
      Dol-P-Glc is undetermined: it lacks any defined catalytic activity and no informative
      molecular-function GO term is assigned. It may reorient (flip) the donor's sugar
      headgroup toward the ER lumen or present the donor to lumenal glycosyltransferases,
      but the biochemical mechanism has not been established.
    boundary: >-
      Its requirement for utilization of the monosaccharide-P-dolichol donors (Dol-P-Man,
      Dol-P-Glc) and its ER-membrane localization are established; the unknown is the
      molecular activity/mechanism, not the pathway or location.
  - gap_statement: >-
      Whether a distinct Dol-P-Glc-selective utilization factor also exists is unresolved,
      as the SL15/Lec35 product was reported to be selective for MPD over GPD, implying an
      additional GPD-selective gene product remains to be identified.
proposed_new_terms: []
references:
- 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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:11179430
  title: Requirement of the Lec35 gene for all known classes of monosaccharide-P-dolichol-dependent
    glycosyltransferase reactions in mammals.
  findings:
  - statement: >-
      Lec35p is required for utilization of the mannose donor Dol-P-Man (MPD) in synthesis
      of both lipid-linked oligosaccharides and glycosylphosphatidylinositols, and is also
      required for MPD-dependent C-mannosylation and GPD-dependent glucosylation of LLO.
    supporting_text: >-
      glucose-P-dolichol (GPD)-dependent glucosylation of LLO. Both were found to require
      Lec35p
  - statement: >-
      Lec35p is not itself the glycosyltransferase; it is not directly required for the
      enzymatic transfer step and instead controls donor orientation in the ER membrane.
    supporting_text: >-
      Lec35p is not directly required for the enzymatic transfer of mannose from the donor
      to the acceptor substrate
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive functional paper (hamster Lec35 = human MPDU1). PubMed-verified;
      establishes the non-catalytic Dol-P-Man/Dol-P-Glc utilization role and ER-membrane
      localization. Abstract-only in cache but the assayed molecular role is clearly stated.
- id: PMID:11733564
  title: MPDU1 mutations underlie a novel human congenital disorder of glycosylation,
    designated type If.
  findings:
  - statement: >-
      MPDU1 mutations cause CDG-If; patient fibroblasts accumulate incomplete LLO
      precursors and normal LLO biosynthesis is restored by expression of wild-type Lec35
      cDNA.
    supporting_text: >-
      Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of
      patients restored normal lipid-linked oligosaccharide biosynthesis
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes MPDU1 as the CDG-If disease gene and links loss of function to defective
      dolichol-linked oligosaccharide biosynthesis. Basis for the TAS/IGI BP annotations.
- id: PMID:16237761
  title: Screening of hepatocyte proteins binding to F protein of hepatitis C virus
    by yeast two-hybrid system.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Yeast two-hybrid screen with HCV F protein as bait (UniProtKB:P0C045); MPDU1 appears
      only as a screen hit. Supports only a bare, non-core protein-binding annotation of
      unclear physiological relevance.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput MS membrane proteome of an NK-like cell line; supports only a generic
      "membrane" localization, not a specific compartment or function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      HuRI records a binary interaction between MPDU1 (O75352) and MANBAL (Q9NQG1),
      consistent with the interaction listed in the UniProt entry.
    supporting_text: reference interactome map of human binary protein interactions
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale binary interactome; the MPDU1-MANBAL interaction is corroborated in
      UniProt but only supports a generic (non-core) protein-binding annotation.
- id: file:human/MPDU1/MPDU1-uniprot.txt
  title: UniProtKB entry O75352 (MPU1_HUMAN)
  findings:
  - statement: >-
      UniProt describes MPDU1 as required for normal utilization of Dol-P-Man in synthesis
      of N-linked and O-linked oligosaccharides and GPI anchors, and as a multi-pass
      membrane protein of the MPDU1 (TC 2.A.43.3) family; loss of function causes CDG1F.
    supporting_text: Required for normal utilization of mannose-dolichol phosphate