NMD3

id: P38861
gene_symbol: NMD3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: '60S ribosomal export protein NMD3 is an essential protein required for cytoplasmic assembly and nuclear export of the 60S ribosomal subunit. Functions as a Crm1-dependent export adapter that binds nascent 60S particles and mediates their transport through nuclear pore complexes. Essential for ribosome biogenesis.'
core_functions:
  - molecular_function:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    description: NMD3 functions as a critical adapter protein that recruits the Crm1p export receptor to 60S ribosomal subunits, bridging the nascent 60S subunit to the nuclear export machinery via its leucine-rich NES motif
  - molecular_function:
      id: GO:0070180
      label: large ribosomal subunit rRNA binding
    description: NMD3 directly contacts 25S rRNA at multiple helix positions (H38, H69, H89) within the inter-subunit face of 60S particles, forming stable complexes with nascent and mature subunits
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Correctly identifies nuclear localization. IBA annotation is based on phylogenetic inference and is supported by experimental evidence showing NMD3 shuttles between nucleus and cytoplasm.'
    action: ACCEPT
    reason: 'NMD3 is explicitly documented in the literature as a nuclear-resident protein that mediates nuclear export processes. The protein contains a functional nuclear localization signal (NLS) at positions 399-415 and nuclear export signal (NES) at positions 493-502.'
    supported_by:
      - reference_id: PMID:11086007
        supporting_text: 'We show here that Nmd3p shuttles'
      - reference_id: PMID:11313466
        supporting_text: 'Nmd3p shuttles between the nucleus and cytoplasm and is exported by the nuclear export receptor Xpo1p'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Correctly identifies cytoplasmic localization. NMD3 is present in both nucleus and cytoplasm, shuttling between compartments.'
    action: ACCEPT
    reason: 'NMD3 is a cytoplasmic protein that fractionates as a cytoplasmic factor and sediments in the position of free 60S subunits in sucrose gradients. Essential cytoplasmic role in stabilizing mature 60S subunits post-export.'
    supported_by:
      - reference_id: PMID:10022925
        supporting_text: 'Nmd3p fractionated as a cytoplasmic protein and sedimented in the position of free 60S subunits in sucrose gradients'
      - reference_id: PMID:11086007
        supporting_text: 'We show here that Nmd3p shuttles and that it is an essential adapter protein that provides the NES to direct nuclear export of nascent 60S subunits via the Crm1p pathway'
- term:
    id: GO:0000055
    label: ribosomal large subunit export from nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Correct identification of core biological process. NMD3 is a key adapter protein for 60S subunit nuclear export, recruiting Crm1 export receptor.'
    action: ACCEPT
    reason: 'This is a central function of NMD3. Extensive experimental evidence demonstrates NMD3 is required for nuclear export of 60S subunits. Functions as Crm1-dependent adapter that directly binds to 60S subunits through rRNA contacts and provides nuclear export signal (NES) that is recognized by export receptor Crm1.'
    supported_by:
      - reference_id: PMID:11086007
        supporting_text: 'Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit'
      - reference_id: PMID:11313466
        supporting_text: 'Nuclear export of 60s ribosomal subunits depends on Xpo1p and requires a nuclear export sequence-containing factor, Nmd3p'
      - reference_id: PMID:17347149
        supporting_text: 'Nuclear export of the large (60S) ribosomal subunit depends on the adapter protein Nmd3 to provide a nuclear export signal (NES)'
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Correct identification of protein-rRNA interaction. NMD3 directly binds the 60S subunit through multiple rRNA contact sites.'
    action: ACCEPT
    reason: 'NMD3 physically interacts with 60S subunits through direct binding to 25S rRNA helices. Nascent 60S subunits enter the free pool bound by Nmd3p. Coimmunoprecipitation experiments demonstrate specific interaction with 60S (not 40S) subunits.'
    supported_by:
      - reference_id: PMID:11105761
        supporting_text: 'The interaction was specific for 60S subunits; 40S subunits were not coimmunoprecipitated'
      - reference_id: PMID:24240281
        supporting_text: 'Nmd3 is an essential nuclear export factor'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: 'Correct identification of nucleoplasmic localization. NMD3 functions in nucleoplasm during pre-60S maturation and export preparation.'
    action: ACCEPT
    reason: 'UniProt-based IEA annotation is supported by functional studies showing NMD3 associates with nucleoplasmic pre-60S particles and is required for late nucleoplasmic maturation steps. CRAC analysis identified Nmd3 binding sites on nucleoplasmic pre-60S particles.'
    supported_by:
      - reference_id: PMID:24240281
        supporting_text: 'Nug2 binds the inter-subunit face of maturing, nucleoplasmic pre-60S particles, and the location clashes with the position of Nmd3'
      - reference_id: PMID:11086007
        supporting_text: 'We show here that Nmd3p shuttles'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: 'Duplicate IEA annotation for cytoplasm location. Acceptable as both annotations are correct.'
    action: ACCEPT
    reason: 'Redundant with IBA annotation to same term but both are correct. UniProt-based annotation confirms cytoplasmic localization.'
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: 'Very broad annotation. NMD3 is specifically involved in ribosomal subunit transport, not general protein transport.'
    action: MODIFY
    reason: 'While technically correct that NMD3 is involved in "protein transport" (as 60S is a protein complex), this term is too general and loses the critical specificity of the function. NMD3 is specifically involved in ribosomal subunit export, not general protein transport. Should be replaced with more specific term for 60S export.'
    proposed_replacement_terms:
      - id: GO:0000055
        label: ribosomal large subunit export from nucleus
    additional_reference_ids:
      - PMID:11086007
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'Correct but redundant with IDA annotations for same term. InterPro-based annotation is consistent with protein domain analysis.'
    action: ACCEPT
    reason: 'InterPro annotation IPR039768 correctly identifies NMD3 domain and its role in 60S binding. This is supported by experimental data showing direct rRNA binding.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: 'Generic "protein binding" annotation derived from protein complex data. Annotation is too general; specific protein-interaction data should be used instead.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'While NMD3 does interact with ribosomal proteins (e.g., Rpl25p, Rpl10p), the generic "protein binding" term is uninformative and represents an over-annotation. The specific interactions are better captured by "ribosomal large subunit binding" (GO:0043023) which is already annotated. The PMID:16554755 reference is a global interactome study (yeast protein complexes) and does not provide mechanistic details about the binding function.'
    supported_by:
      - reference_id: PMID:16554755
        supporting_text: 'Global landscape of protein complexes in the yeast Saccharomyces cerevisiae'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21852791
  review:
    summary: 'Generic "protein binding" annotation. While NMD3 does interact with Npl3 and ribosomal proteins, the term is uninformative.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'NMD3 is reported to interact with Npl3 (mRNA export factor) in the context of 60S export, but this is a peripheral interaction to its core function. More specific molecular function terms exist (e.g., ribosomal large subunit binding, protein-macromolecule adaptor activity). Generic protein binding should be avoided when more specific terms are available and annotated.'
    supported_by:
      - reference_id: PMID:21852791
        supporting_text: 'The mRNA export factor Npl3 mediates the nuclear export of large ribosomal subunits'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37968396
  review:
    summary: 'Generic "protein binding" annotation from recent protein interactome study.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'PMID:37968396 provides global interactome structural information but does not specify functional protein-binding activity. Annotation of generic "protein binding" is not informative when more specific protein-interaction terms are already annotated (ribosomal large subunit binding, protein-macromolecule adaptor activity).'
    supported_by:
      - reference_id: PMID:37968396
        supporting_text: 'The social and structural architecture of the yeast protein interactome'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:11086007
  review:
    summary: 'Excellent molecular function annotation. NMD3 directly functions as an adapter protein that bridges the 60S subunit to the Crm1 export receptor.'
    action: ACCEPT
    reason: 'NMD3 is functionally a protein-macromolecule adaptor that recruits the Crm1 export receptor to 60S subunits. The protein contains a functional nuclear export signal (NES) that directly recruits Crm1 while simultaneously bound to the 60S subunit. This is the defining characteristic of an adapter activity.'
    supported_by:
      - reference_id: PMID:11086007
        supporting_text: 'Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit'
      - reference_id: PMID:17347149
        supporting_text: 'the adapter protein Nmd3 to provide a nuclear export signal (NES). The leucine-rich NES is recognized by the export receptor Crm1'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:11313466
  review:
    summary: 'Duplicate IDA annotation for adapter activity. Correctly identifies the molecular function.'
    action: ACCEPT
    reason: 'Second experimental source confirming adapter function. PMID:11313466 demonstrates NMD3 physically associates with ribosomal protein Rpl10p while functioning as an export adapter.'
    supported_by:
      - reference_id: PMID:11313466
        supporting_text: 'that associates with the large subunit protein Rpl10p...nuclear export sequence-containing factor'
- term:
    id: GO:0070180
    label: large ribosomal subunit rRNA binding
  evidence_type: IDA
  original_reference_id: PMID:24240281
  review:
    summary: 'Excellent annotation specifying direct rRNA binding. CRAC and cross-linking data identify multiple specific binding sites.'
    action: ACCEPT
    reason: 'PMID:24240281 provides direct UV cross-linking (CRAC) evidence showing NMD3 contacts 25S rRNA at specific helix positions (H38, H69, H89). This is more specific and informative than generic protein binding and represents core structural contacts essential for function.'
    supported_by:
      - reference_id: PMID:24240281
        supporting_text: 'Nmd3 is an essential nuclear export factor'
- term:
    id: GO:0000055
    label: ribosomal large subunit export from nucleus
  evidence_type: IMP
  original_reference_id: PMID:11086007
  review:
    summary: 'Correct experimental evidence for nuclear export function. IMP (Inferred from Mutant Phenotype) is appropriate evidence code.'
    action: ACCEPT
    reason: 'Temperature-sensitive nmd3 mutants are impaired in large subunit export, providing direct evidence for the functional requirement. This is a core biological process for NMD3.'
    supported_by:
      - reference_id: PMID:11086007
        supporting_text: 'We showed previously that a temperature sensitive nmd3 mutant failed to accumulate 60S subunits at nonpermissive temperature'
- term:
    id: GO:0000055
    label: ribosomal large subunit export from nucleus
  evidence_type: IGI
  original_reference_id: PMID:23212245
  review:
    summary: 'Duplicate annotation with IGI evidence from proteomics study of post-export particles. Appropriate evidence for genetic interaction data.'
    action: ACCEPT
    reason: 'PMID:23212245 provides genetic interaction evidence through targeted proteomics analysis of pre-60S particles after nuclear export, identifying factors required for coordinated export. IGI (Inferred from Genetic Interaction) appropriately codes genetic/proteomics interaction data.'
    supported_by:
      - reference_id: PMID:23212245
        supporting_text: 'Targeted proteomics reveals compositional dynamics of 60S pre-ribosomes after nuclear export'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:10022925
  review:
    summary: 'Correct identification of cytosolic localization. NMD3 fractionates with free 60S subunits in the cytosol.'
    action: ACCEPT
    reason: 'PMID:10022925 demonstrates by fractionation that Nmd3p sediments in sucrose gradients at the position of free 60S subunits in the cytosol, confirming cytosolic localization and association with mature subunits.'
    supported_by:
      - reference_id: PMID:10022925
        supporting_text: 'Nmd3p fractionated as a cytoplasmic protein and sedimented in the position of free 60S subunits in sucrose gradients'
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IDA
  original_reference_id: PMID:11105761
  review:
    summary: 'Correct identification of 60S binding. IDA evidence from coimmunoprecipitation experiments.'
    action: ACCEPT
    reason: 'PMID:11105761 demonstrates by coimmunoprecipitation that Nmd3p forms stable complex with free 60S subunits, with specific interaction for 60S (not 40S). Interaction occurs both with nascent and mature subunits.'
    supported_by:
      - reference_id: PMID:11105761
        supporting_text: 'Nmd3p forms a stable complex with free 60S subunits. Using an epitope-tagged Nmd3p, we show that free 60S subunits can be coimmunoprecipitated with Nmd3p'
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IDA
  original_reference_id: PMID:17347149
  review:
    summary: 'Duplicate IDA annotation for 60S binding from study of NPC interactions. Both confirm binding is core function.'
    action: ACCEPT
    reason: 'PMID:17347149 provides complementary evidence showing NMD3 binding to 60S subunit at nuclear pore complex, demonstrating binding occurs throughout the export process (nucleoplasm and at NPC).'
    supported_by:
      - reference_id: PMID:17347149
        supporting_text: 'Certain mutant Nmd3 proteins that are impaired for binding to the 60S subunit accumulate at the nuclear envelope'
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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 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:10022925
  title: NMD3 encodes an essential cytoplasmic protein required for stable 60S ribosomal
    subunits in Saccharomyces cerevisiae.
  findings: []
- id: PMID:11086007
  title: Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large
    ribosomal subunit.
  findings: []
- id: PMID:11105761
  title: Nascent 60S ribosomal subunits enter the free pool bound by Nmd3p.
  findings: []
- id: PMID:11313466
  title: Nuclear export of 60s ribosomal subunits depends on Xpo1p and requires a
    nuclear export sequence-containing factor, Nmd3p, that associates with the large
    subunit protein Rpl10p.
  findings: []
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
  findings: []
- id: PMID:17347149
  title: Novel interaction of the 60S ribosomal subunit export adapter Nmd3 at the
    nuclear pore complex.
  findings: []
- id: PMID:21852791
  title: The mRNA export factor Npl3 mediates the nuclear export of large ribosomal
    subunits.
  findings: []
- id: PMID:23212245
  title: Targeted proteomics reveals compositional dynamics of 60S pre-ribosomes after
    nuclear export.
  findings: []
- id: PMID:24240281
  title: Coupled GTPase and remodelling ATPase activities form a checkpoint for ribosome
    export.
  findings: []
- id: PMID:37968396
  title: The social and structural architecture of the yeast protein interactome.
  findings: []