id: Q8N4V1
gene_symbol: MMGT1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: MMGT1 (ER membrane protein complex subunit 5, EMC5; also known as membrane magnesium transporter 1 / TMEM32) is a small (131 aa) polytopic ER membrane protein with two transmembrane helices and cytoplasmic N- and C-termini. It is a constitutive subunit of the ER membrane protein complex (EMC), a conserved transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. Within the complex, EMC5 packs against the catalytic insertase subunits EMC3 and EMC6 that form the hydrophilic membrane vestibule through which substrate transmembrane domains are inserted. The EMC enables the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or contain destabilizing charged or aromatic residues. It mediates post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins, including setting the N-exo topology of the first transmembrane domain of G protein-coupled receptors. MMGT1 localizes to the ER membrane and is broadly expressed. Its legacy designation as a membrane magnesium transporter derives from overexpression studies of the rodent ortholog and is not supported by a defined transport mechanism for the human protein.
alternative_products:
- name: '1'
  id: Q8N4V1-1
- name: '2'
  id: Q8N4V1-2
  sequence_note: VSP_036488
existing_annotations:
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Generic transmembrane transporter activity propagated phylogenetically from the legacy "membrane magnesium transporter" family inference. The verified function of MMGT1 is as an EMC insertase subunit, not as a solute transporter.
    action: MARK_AS_OVER_ANNOTATED
    reason: No experimental evidence that human MMGT1 transports a solute; the transporter assignment derives from a legacy family name and is superseded by the EMC insertase role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic early-endosome localization, ultimately derived from the rodent ortholog. The experimentally verified compartment is the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization carried over by similarity but peripheral to the core ER-membrane EMC site of action.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Early endosome membrane
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic Golgi localization derived from the rodent ortholog. The core EMC site of action is the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity but peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Golgi
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic plasma-membrane localization, weakly supported and most likely reflecting the transporter-family inference. MMGT1 acts in the ER membrane as an EMC subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not supported by experimental evidence for the human protein; inconsistent with the ER-membrane EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: MMGT1/EMC5 is a constitutive subunit of the ER membrane protein complex; phylogenetic assignment is consistent with direct experimental and structural evidence. Core structural identity.
    action: ACCEPT
    reason: EMC complex membership is the core cellular-component identity of MMGT1; supported by IDA, cryo-EM structures, and the conserved EMC5 family.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of a Golgi membrane location from the UniProt subcellular location vocabulary, itself a By-similarity assignment from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the core ER-membrane EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Golgi
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ER membrane subcellular location from UniProt; the correct and core compartment for MMGT1.
    action: ACCEPT
    reason: Correct core location; redundant with experimental EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006824
    label: cobalt ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inter-ontology electronic inference of cobalt ion transport, derived ultimately from the legacy metal-transporter family assignment. No experimental support for cobalt transport by human MMGT1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative metal-transport process inferred from a contested family name; not the verified EMC insertase function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA machine-learning assignment to the endomembrane system, a generic parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the ER membrane term captures the informative localization.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of early endosome membrane localization from UniProt, a By-similarity assignment from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Early endosome membrane
- term:
    id: GO:0034755
    label: iron ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inter-ontology electronic inference of iron transmembrane transport from the legacy metal-transporter family. No experimental support for iron transport by human MMGT1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative metal-transport process; not the verified EMC insertase function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Generic transmembrane transport process inferred electronically from the transporter-activity assignment. Not the verified EMC insertase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from the contested transporter-family inference; superseded by the EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:1903830
    label: magnesium ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inter-ontology electronic inference of magnesium transmembrane transport. UniProt records only a By-similarity possibility of Mg(2+) transport for human MMGT1; the consensus role is as an EMC insertase subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative, By-similarity metal transport not demonstrated for the human protein; not a core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: IntAct interactions from the foundational ERAD-network mapping study that first defined the EMC, including the EMC subunits EMC2 and EMC6. Genuine EMC partnership, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real EMC partner interactions but the bare protein binding term is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q9BV81: EMC6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Quantitative interactome (stoichiometry/abundance) capture; reflects EMC and membrane-protein partnerships. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome (BioPlex protein communities) capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary (HuRI) interactome captures of MMGT1 with multiple membrane proteins, many plausibly EMC clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions partly reflecting client engagement; the bare term is uninformative and not core.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q9Y3D6: FIS1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: enables
  review:
    summary: Interaction evidence from the cryo-EM structural study of the human EMC, reflecting genuine intra-complex partnerships. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interaction; the EMC complex membership term captures the informative content.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q9BV81: EMC6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-MS interactome capture. Genuine partners but the bare term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40355756
  qualifier: enables
  review:
    summary: Solute carrier (SLC) superfamily interactome capture; many SLC partners are plausible EMC clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions partly reflecting client engagement; the bare term is uninformative and not core.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'Q8N4V1; Q969S0: SLC35B4'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined-IEA assignment of cytoplasm; MMGT1 is an integral ER membrane protein. Cytoplasm is an imprecise parent relative to the experimentally supported ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic and imprecise; the specific compartment is the ER membrane.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-Compara electronic transfer of early endosome localization from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Early endosome membrane
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-Compara electronic transfer of Golgi localization from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Golgi
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-Compara electronic transfer of plasma membrane localization; weakly supported and most likely reflecting transporter-family inference.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not supported experimentally for the human protein; inconsistent with the ER-membrane EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0015087
    label: cobalt ion transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-Compara transfer of a cobalt transporter activity from the rodent ortholog. No experimental support for cobalt transport by human MMGT1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative metal-transporter activity from the contested family inference; superseded by the EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0015093
    label: ferrous iron transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-Compara transfer of a ferrous iron transporter activity from the rodent ortholog. No experimental support for iron transport by human MMGT1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative metal-transporter activity; superseded by the EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0015095
    label: magnesium ion transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-Compara transfer of magnesium transporter activity from the rodent ortholog. UniProt records only a By-similarity possibility of Mg(2+) transport; the consensus role is as an EMC insertase subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative, By-similarity metal transport not demonstrated for the human protein; not a core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-Compara transfer of generic transmembrane transporter activity from the rodent ortholog. Not the verified EMC insertase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from the contested transporter-family inference; superseded by the EMC role.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator ISS transfer of Golgi membrane localization from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Golgi
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization from the EMC-discovery ERAD-network study. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator ISS transfer of early endosome membrane localization from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Early endosome membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:29242231
  qualifier: located_in
  review:
    summary: NAS annotation of ER membrane localization for the EMC from the insertase study, consistent with experimental evidence and the core compartment of MMGT1.
    action: ACCEPT
    reason: Correct core location; consistent with EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IDA
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: The EMC inserts transmembrane domains, including stop-transfer membrane-anchor sequences of multipass proteins; MMGT1/EMC5 is part of the insertase. A core biological process of the EMC.
    action: ACCEPT
    reason: Core EMC-mediated process; MMGT1 contributes as a constitutive subunit, and EMC5 depletion reduces client insertion.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: The ER membrane protein complex is a transmembrane domain insertase
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: The EMC mediates post-translational insertion of tail-anchored proteins; demonstrated directly with the reconstituted complex. A core EMC process to which MMGT1 contributes as a subunit.
    action: ACCEPT
    reason: Core EMC-mediated process; directly demonstrated.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: The ER membrane protein complex is a transmembrane domain insertase
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: part_of
  review:
    summary: ComplexPortal/structural IPI assignment of EMC complex membership based on the cryo-EM structure of the human EMC. Core structural identity of MMGT1.
    action: ACCEPT
    reason: Structurally demonstrated core EMC membership.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:34918864
  qualifier: contributes_to
  review:
    summary: In vivo Drosophila evidence that the EMC, including EMC5, is required for TMD membrane insertion of a tail-anchored client. MMGT1 is a small non-catalytic membrane subunit, so the insertase activity is a complex-level property to which it contributes.
    action: KEEP_AS_NON_CORE
    reason: contributes_to is appropriate, but MMGT1 is not the catalytic insertase subunit (EMC3/EMC6 form the vestibule); the core MMGT1 identity is EMC membership and ER-membrane localization.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: energy-independent insertion into endoplasmic
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:34918864
  qualifier: involved_in
  review:
    summary: In vivo (Drosophila) IMP evidence that the EMC, including EMC5, is required for tail-anchored protein insertion. Core EMC process.
    action: ACCEPT
    reason: Core EMC process; supported by in vivo loss-of-function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP evidence that EMC subunit depletion impairs membrane insertion; MMGT1 contributes to the complex-level insertase activity but is not the catalytic subunit.
    action: KEEP_AS_NON_CORE
    reason: contributes_to is appropriate; complex-level catalysis by EMC3/EMC6, so not MMGT1's standalone core MF.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: energy-independent insertion into endoplasmic
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: contributes_to
  review:
    summary: IMP evidence (topogenesis study) supporting the EMC's membrane insertase activity, to which MMGT1 contributes as a subunit.
    action: KEEP_AS_NON_CORE
    reason: contributes_to is appropriate; complex-level catalysis, not MMGT1's standalone core MF.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: energy-independent insertion into endoplasmic
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: involved_in
  review:
    summary: The EMC is required for cotranslational insertion of multipass proteins in which stop-transfer membrane-anchor sequences become membrane-spanning helices; MMGT1 is part of the insertase. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process; supported by IMP of EMC subunits.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32439656
  qualifier: located_in
  review:
    summary: Direct (structural) evidence placing MMGT1 in the ER membrane. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: involved_in
  review:
    summary: IMP (topogenesis study) supporting the EMC's role in insertion of stop-transfer membrane-anchor sequences and N-exo topogenesis of multipass clients. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: IMP evidence that the EMC is required for tail-anchored protein insertion into the ER membrane; MMGT1 is part of the insertase. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process; directly demonstrated.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane-proteome detection (NK cell membrane proteome); a generic membrane localization, a parent of the specific ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the ER membrane term captures the informative localization.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct generic membrane localization from the EMC-discovery study; a parent of the specific ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the ER membrane term captures the informative localization.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: part_of
  review:
    summary: Direct experimental identification of MMGT1/EMC5 in the EMC by the foundational ERAD-network mapping study. Core structural identity.
    action: ACCEPT
    reason: Core EMC membership; directly demonstrated.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator ISS transfer of early endosome localization from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Early endosome membrane
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator ISS transfer of Golgi localization from the rodent ortholog.
    action: KEEP_AS_NON_CORE
    reason: Possible minor localization by similarity; peripheral to the ER-membrane EMC core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: Golgi
- term:
    id: GO:0015095
    label: magnesium ion transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Curator ISS transfer of magnesium transporter activity from the rodent ortholog. UniProt records only a By-similarity possibility of Mg(2+) transport; the consensus role is as an EMC insertase subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative, By-similarity metal transport not demonstrated for the human protein; not a core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
- term:
    id: GO:0015693
    label: magnesium ion transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator ISS transfer of a magnesium transport process from the rodent ortholog. Not demonstrated for the human protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative, By-similarity metal transport; superseded by the EMC insertase role and not a core function.
    supported_by:
    - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
      supporting_text: May be involved in Mg(2+) transport (By similarity)
core_functions:
- description: Constitutive small membrane subunit of the ER membrane protein complex (EMC), localizing to the ER membrane as part of the insertase that mediates energy-independent insertion of transmembrane domains.
  molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  in_complex:
    id: GO:0072546
    label: EMC complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
    supporting_text: Component of the ER membrane protein complex (EMC).
  - reference_id: PMID:29242231
    supporting_text: The ER membrane protein complex is a transmembrane domain insertase
  - reference_id: PMID:38517390
    supporting_text: Endogenous human EMC was purified via a Twin-Strep tag on EMC5, confirming EMC5/MMGT1 as a stable core membrane subunit of the complex.
    full_text_unavailable: true
- description: As part of the EMC, contributes to post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins at the ER membrane.
  molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/MMGT1/MMGT1-uniprot.txt
    supporting_text: post-translational insertion of tail-anchored/TA proteins in
  - reference_id: PMID:37957425
    supporting_text: >-
      Thus, multipass membrane proteins can be released by the ribosome-translocon complex in
      an incompletely inserted state, requiring a separate EMC-mediated post-translational
      insertion step to rectify their topology, complete biogenesis and evade quality control.
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  - id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
proposed_new_terms: []
references:
- id: PMID:32459176
  title: The architecture of EMC reveals a path for membrane protein insertion.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'O''Donnell et al. 2020 (eLife). Cryo-EM architecture of the human EMC,
      establishing the overall complex organization and subunit topology relevant to
      MMGT1 as a constitutive EMC subunit.'
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  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; source of a generic membrane localization.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: Affinity-MS ERAD-network mapping that first identified the EMC (including MMGT1/EMC5) in human cells and localized it to the ER membrane.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational identification of the human EMC; source of EMC membership and ER membrane localization for MMGT1.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Quantitative interactome; source of an IPI protein-binding annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome; source of an IPI protein-binding annotation.
- id: PMID:29242231
  title: The ER membrane protein complex is a transmembrane domain insertase.
  findings:
  - statement: EMC is a transmembrane domain insertase; depletion of EMC5/EMC6 reduces client insertion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the insertase function of the EMC; implicates EMC5 directly in insertion.
- id: PMID:29809151
  title: The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
  findings:
  - statement: The EMC engages multipass membrane protein clients cotranslationally to enable their biogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cotranslational multipass biogenesis role of the EMC.
- id: PMID:30415835
  title: EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  findings:
  - statement: The EMC sets the N-exo topology of the first TMD of GPCRs and other multipass proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Topogenesis/orientation role of the EMC.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI binary interactome; source of IPI protein-binding partners.
- id: PMID:32439656
  title: Structural basis for membrane insertion by the human ER membrane protein complex.
  findings:
  - statement: Cryo-EM structure of the human EMC; defines MMGT1/EMC5 topology and intra-complex contacts.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis for the EMC; abstract-only in cache.
- 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 affinity-MS interactome; source of an IPI protein-binding annotation.
- id: PMID:34918864
  title: EMC is required for biogenesis of Xport-A, an essential chaperone of Rhodopsin-1 and the TRP channel.
  findings:
  - statement: In vivo Drosophila evidence that the EMC, including EMC5, is required for TMD membrane insertion of a tail-anchored client.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: In vivo loss-of-function support for the EMC insertase function; basis for the FlyBase IMP annotations.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell interactome/localization; source of an IPI protein-binding annotation.
- id: PMID:40355756
  title: The solute carrier superfamily interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: SLC interactome; SLC partners are plausible EMC clients; source of an IPI protein-binding annotation.
- id: PMID:37199759
  title: A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.
  findings:
  - statement: The EMC hydrophilic vestibule acts as a charge-based selectivity filter that rejects mitochondrial tail-anchored proteins and enforces the positive-inside rule for multipass substrates; EMC5/MMGT1 is a core membrane subunit of this insertase/selectivity machine.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2023). Recent mechanistic refinement of the EMC insertase (selectivity filter/topology enforcement); contextualizes EMC5 as a core membrane component, though the tested charged residues are on EMC3.
- id: PMID:37196677
  title: "EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate."
  findings:
  - statement: Cryo-EM of an EMC-bound CaV1.2 assembly intermediate shows the EMC functions as a holdase/chaperone during multipass channel assembly, extending EMC function beyond insertion; EMC5 is a constitutive core subunit of this machine.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nature 2023). High-authority example of the EMC holdase/chaperone mode for a multipass client; supports the complex-level functions to which EMC5 contributes.
- id: PMID:37957425
  title: EMC rectifies the topology of multipass membrane proteins.
  findings:
  - statement: C-terminal TMDs of mammalian multipass proteins are inserted post-translationally by the EMC to rectify topology and complete biogenesis; this sequential co-/post-translational mechanism may apply to ~250 diverse multipass proteins. EMC5 is a core subunit of the EMC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Struct Mol Biol 2023/2024). Expands the EMC client repertoire and topology-completion role; supports the stop-transfer/multipass insertion processes to which EMC5 contributes as a core subunit.
- id: PMID:38517390
  title: Structural insights into human EMC and its interaction with VDAC.
  findings:
  - statement: Cryo-EM structures of human EMC in apo and VDAC-bound states reveal a gating plug in the hydrophilic vestibule and an EMC-VDAC interaction at mitochondria-ER contact sites; endogenous human EMC was purified via a Twin-Strep tag on EMC5, showing EMC5 is a tractable handle for native EMC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Aging 2024). Human EMC structure; EMC5 used as the affinity handle for native complex purification, confirming EMC5 as a stable core membrane subunit; also documents an EMC-VDAC interaction at MERCs.
- id: PMID:40753078
  title: The EMC acts as a chaperone for membrane proteins.
  findings:
  - statement: Beyond TMD insertase activity, the EMC has a chaperone function engaging TMDs via its EMC1 subunit and modulating their orientation in the bilayer; productive TMD assembly reduces binding to the chaperone site. EMC5 is a core EMC subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2025). Defines an additional EMC chaperone mode (client features, EMC1-mediated TMD engagement); supports the broader membrane-protein biogenesis role of the EMC of which EMC5 is a core member.
- id: PMID:37269834
  title: Identification of host regulators of Mycobacterium tuberculosis phenotypes uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence.
  findings:
  - statement: A genome-wide CRISPR screen prioritized MMGT1; MMGT1-deficient macrophages promote a switch of M. tuberculosis toward persistence, with upregulated lipid metabolism and lipid droplet accumulation driven by the orphan GPCR GPR156, and triacylglycerol-synthesis inhibition reduces both droplets and persistence.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Cell Host Microbe 2023). MMGT1-specific host-pathogen phenotype (lipid droplet/persistence axis); the study does not resolve whether the mechanism is via EMC function, magnesium transport, or another pathway, so recorded as informative context rather than a core molecular function.
suggested_questions:
- question: Does human MMGT1/EMC5 have any genuine magnesium (or other metal) transport activity in its physiological ER context, or is the reported metal transport an overexpression artifact unrelated to its EMC function?
- question: What is the specific structural contribution of EMC5 to stability and substrate gating of the EMC3/EMC6 insertase vestibule?
suggested_experiments:
- description: Reconstitute purified EMC with and without EMC5 into proteoliposomes and assay both model TMD insertion and putative Mg2+ flux, to separate any intrinsic transport activity from the insertase function.
- description: Quantitative membrane proteomics of EMC5-knockout versus rescued cells to define the EMC5-dependent client repertoire and test whether magnesium homeostasis phenotypes are direct or secondary to impaired client biogenesis.