Affinage

NGDN

Neuroguidin · UniProt Q8NEJ9

Round 2 corrected
Length
315 aa
Mass
35.9 kDa
Annotated
2026-04-29
46 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NGDN (neuroguidin/CANu1) is a nucleolar RNA-binding protein that functions in ribosome biogenesis and translational control. Within the nucleolus, NGDN assembles with AATF and NOL10 into the salt-stable trimeric ANN complex via its UTP3/SAS10 domain; all three subunits are mutually required for stability and for pre-rRNA cleavage at the 5'ETS and ITS1 sites that generate mature 18S rRNA for 40S subunit biogenesis (PMID:27599843, PMID:9814757). Loss of NGDN triggers ribosomal stress, p53 induction, G1 arrest, and sensitization to DNA-damaging agents (PMID:18547334, PMID:21266106). In hippocampal dendrites, NGDN acts as a translation-inhibitory factor within the CPEB polyadenylation complex, opposing poly(A) polymerase Gld2 to suppress local mRNA polyadenylation and restrain protein synthesis-dependent long-term potentiation (PMID:22727665).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1998 High

    Establishing that the NGDN ortholog Lcp5p is a nucleolar factor required for the earliest pre-rRNA cleavage events (A0–A2) answered whether this protein family participates in small ribosomal subunit biogenesis.

    Evidence Genetic depletion, pre-rRNA processing assays, polysome analysis, snoRNA co-IP, and immunofluorescence in S. cerevisiae

    PMID:9814757

    Open questions at the time
    • Mammalian ortholog function not yet tested
    • Direct RNA-binding sites on pre-rRNA unknown
    • Mechanism by which Lcp5p promotes cleavage undefined
  2. 2008 Medium

    Demonstrating that human NGDN (CANu1) localizes to nucleoli and that its depletion causes ribosomal stress, p53 activation, and G1 arrest extended the yeast findings to a conserved mammalian ribosome biogenesis function and linked it to cell-cycle control.

    Evidence GFP-fusion imaging, siRNA knockdown, flow cytometry, immunoblotting for p53 and B23 in human cells

    PMID:18547334

    Open questions at the time
    • Specific rRNA processing step affected in human cells not mapped
    • Whether p53 induction is direct or secondary to ribosomal stress not distinguished
    • UV-induced translocation mechanism unclear
  3. 2011 Medium

    Showing that NGDN depletion sensitizes cells to doxorubicin-induced apoptosis with p21 induction and caspase activation revealed that ribosomal stress from NGDN loss cooperates with DNA damage signaling.

    Evidence shRNA knockdown, viability/apoptosis assays, immunoblotting for p21 and cleaved PARP, caspase-3/7 activity in U2OS cells

    PMID:21266106

    Open questions at the time
    • Causal relationship between rRNA processing defect and drug sensitivity not formally tested
    • Whether NGDN has a direct role in DNA damage response versus indirect ribosomal stress remains unresolved
  4. 2012 High

    Identifying NGDN as a translation-inhibitory factor within the dendritic CPEB–Gld2–PARN complex that controls NR2A mRNA polyadenylation and LTP established a second, cytoplasmic role for NGDN distinct from ribosome biogenesis.

    Evidence Co-immunoprecipitation, shRNA knockdown in hippocampal neurons, dendritic polyadenylation assays, in vivo LTP electrophysiology

    PMID:22727665

    Open questions at the time
    • Full repertoire of CPEB-target mRNAs regulated by NGDN unknown
    • Structural basis of NGDN–CPEB interaction unresolved
    • How NGDN partitions between nucleolar and dendritic pools unclear
  5. 2012 Medium

    UV-crosslinking interactome capture confirmed NGDN as an in vivo mRNA-binding protein in human cells, consistent with its dual roles in rRNA and mRNA metabolism.

    Evidence UV crosslinking, oligo(dT) purification, quantitative mass spectrometry in HeLa cells

    PMID:22658674

    Open questions at the time
    • Specific mRNA targets bound by NGDN not identified
    • Whether mRNA binding reflects cytoplasmic CPEB function, nucleolar function, or both is unknown
  6. 2016 High

    Biochemical characterization of the salt-stable ANN complex (AATF–NGDN–NOL10), with domain-mapping showing the UTP3/SAS10 domain of NGDN is essential for assembly, and demonstration that all three subunits are required for 5'ETS and ITS1 cleavage, defined the molecular unit through which NGDN acts in 40S maturation.

    Evidence Co-IP/domain-mapping pulldowns, siRNA depletion of each member, Northern blot and pulse-chase pre-rRNA processing in human cells

    PMID:27599843

    Open questions at the time
    • How the ANN complex is recruited to the pre-ribosomal particle in human cells unknown
    • Whether additional factors bridge ANN to the U3 snoRNP not determined
  7. 2022 High

    Cryo-EM structure of the yeast Bfr2–Lcp5 module within the 90S processome provided the first atomic-level view of how the NGDN ortholog integrates into the ribosome assembly machinery and revealed an interaction architecture resembling the exosome cofactor Rrp6–Rrp47 pair.

    Evidence Cryo-EM (3.99–7.24 Å), AlphaFold-assisted modeling, circular dichroism, protein–protein interaction assays in yeast

    PMID:35650250

    Open questions at the time
    • Human ANN complex structure not yet determined
    • Functional significance of the Rrp6–Rrp47-like architecture for processome transitions not tested in vivo
    • How post-translational modifications regulate the Bfr2–Lcp5 module unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NGDN partitions between its nucleolar ribosome biogenesis role and its cytoplasmic CPEB-dependent translational control role, whether cell-type-specific mechanisms govern this partitioning, and whether a high-resolution structure of the human ANN complex can be obtained remain major open questions.
  • No structural data for the human ANN complex
  • Regulatory signals controlling NGDN nucleolar vs. dendritic localization unknown
  • Physiological consequences of NGDN loss in vivo (knockout animal) not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0045182 translation regulator activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005730 nucleolus 3 GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-112316 Neuronal System 1
Partners
AATFCPEB1NOL10PAPD4PARN
Complex memberships
90S small subunit processome (yeast ortholog)ANN complex (AATF–NGDN–NOL10)CPEB polyadenylation complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 The yeast ortholog of NGDN, Lcp5p (LCP5), localizes predominantly to the nucleolus and is required for early pre-rRNA cleavage steps (A0–A2) that produce mature 18S rRNA. Depletion of Lcp5p impairs pre-rRNA processing, reduces polysome levels, and antibodies against Lcp5p immunoprecipitate the U3 snoRNA (snR17), indicating direct involvement in the small subunit processome. Genetic depletion, in vivo pre-rRNA processing assays, polysome analysis, indirect immunofluorescence, co-immunoprecipitation of snoRNA RNA (New York, N.Y.) High 9814757
2008 Human NGDN (CANu1) localizes to nucleoli via its C-terminal domain, is required for maintenance of ribosomal structure, and its siRNA-mediated silencing causes ribosomal stress leading to G1 cell-cycle arrest, induction of p53, and translocation of B23 (nucleophosmin) from nucleolus to nucleoplasm. Upon UV damage, CANu1 translocates from nucleolus to nuclear foci with increased mobility. GFP-fusion localization, siRNA knockdown, cell-cycle analysis (flow cytometry), immunoblotting for p53 and B23, FRAP after UV damage Genes to cells : devoted to molecular & cellular mechanisms Medium 18547334
2011 shRNA-mediated depletion of Neuroguidin/CANu1 (NGDN) in human osteosarcoma U2OS cells sensitizes them to doxorubicin, increasing apoptosis ~3-fold. Mechanistically, NGDN depletion induces p21 expression and PARP cleavage and elevates caspase-3/7 activity. In the presence of doxorubicin, NGDN translocates from nucleolus to nuclear foci. shRNA knockdown, cell viability assay, apoptosis assay, immunoblotting (p21, cleaved PARP), caspase-3/7 activity assay, fluorescence microscopy BMB reports Medium 21266106
2012 Neuroguidin (Ngd/NGDN) functions as a translation inhibitory factor within a dendritic CPEB-associated polyadenylation complex together with poly(A) polymerase Gld2 and deadenylase PARN. Ngd opposes Gld2 in controlling dendritic mRNA polyadenylation: shRNA depletion of Ngd enhances NR2A (NMDA receptor subunit) expression in dendrites and potentiates protein synthesis-dependent long-term potentiation (LTP) at hippocampal dentate gyrus synapses. Co-immunoprecipitation, shRNA knockdown in neurons, dendritic polyadenylation assays, immunofluorescence, in vivo LTP electrophysiology Molecular cell High 22727665
2016 Human NGDN (neuroguidin) forms a salt-stable trimeric complex with AATF/Che-1 and NOL10, termed the ANN complex, all localized to nucleoli. The UTP3/SAS10 domain of NGDN and the WD40 repeats of NOL10 are required for complex formation, as shown by domain-mapping experiments. All three members are mutually dependent for protein stability. The ANN complex is required for nucleolar processing of pre-rRNA at the 5'ETS and ITS1 cleavage sites, supporting 40S ribosomal subunit maturation and 18S rRNA production. Co-immunoprecipitation/immunoprecipitation (salt-stable complex), domain-mapping pulldowns, siRNA depletion of each member, pre-rRNA processing assays (Northern blot/pulse-chase), nucleolar localization by immunofluorescence Nucleic acids research High 27599843
2022 The cryo-EM structure of the yeast Bfr2-Lcp5 complex (ortholog of the NGDN-containing module) was determined at 3.99–7.24 Å resolution within the 90S small subunit processome. The Bfr2-Lcp5 interaction interface was structurally characterized using AlphaFold-assisted modeling, validated by circular dichroism of recombinant proteins and protein-protein interaction assays. The complex interaction architecture resembles that of the exosome factors Rrp6-Rrp47, and the module regulates transitions of the 90S processome. CryoEM structure determination (3.99–7.24 Å), AlphaFold-assisted modeling, circular dichroism of recombinant proteins, protein-protein interaction validation Communications biology High 35650250
2012 NGDN was identified as a component of the mRNA-bound proteome (mRNA interactome) of human HeLa cells by UV crosslinking and oligo(dT) purification coupled with quantitative proteomics, indicating it physically associates with mRNA in vivo. UV crosslinking, oligo(dT) purification, quantitative mass spectrometry (interactome capture) Cell Medium 22658674
2006 NGDN was identified among proteins phosphorylated in vivo on the human mitotic spindle, as detected by mass spectrometry-based phosphoproteomics of purified mitotic spindles. Mass spectrometry-based phosphoproteomics from purified human mitotic spindles Proceedings of the National Academy of Sciences of the United States of America Low 16565220

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2006 Phosphoproteome analysis of the human mitotic spindle. Proceedings of the National Academy of Sciences of the United States of America 281 16565220
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2018 An orthogonal proteomic survey uncovers novel Zika virus host factors. Nature 143 30177828
2016 FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3. Cell reports 137 27926873
2014 The central role of EED in the orchestration of polycomb group complexes. Nature communications 131 24457600
2010 RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity. The Journal of biological chemistry 131 21081503
2012 Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. Molecular cell 123 22727665
1997 II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. The Journal of pharmacology and experimental therapeutics 123 9262371
2021 Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Molecular cell 105 33545068
2018 Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. Cancer cell 101 29478914
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
1998 Synthetic lethal interactions with conditional poly(A) polymerase alleles identify LCP5, a gene involved in 18S rRNA maturation. RNA (New York, N.Y.) 44 9814757
1997 I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. The Journal of pharmacology and experimental therapeutics 43 9262370
2018 Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age-associated insulin resistance. Aging cell 40 29901258
2019 Metabolism and biochemical properties of nicotinamide adenine dinucleotide (NAD) analogs, nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD). Scientific reports 29 31511627
2013 The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats. PloS one 28 24040053
2016 Human AATF/Che-1 forms a nucleolar protein complex with NGDN and NOL10 required for 40S ribosomal subunit synthesis. Nucleic acids research 23 27599843
2018 Measuring CD38 Hydrolase and Cyclase Activities: 1,N6-Ethenonicotinamide Adenine Dinucleotide (ε-NAD) and Nicotinamide Guanine Dinucleotide (NGD) Fluorescence-based Methods. Bio-protocol 18 30112426
1999 NGD 94-1 as an agonist at human recombinant dopamine D4.4 receptors expressed in HEK293 cells. European journal of pharmacology 18 10395031
2011 Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist. Journal of medicinal chemistry 10 21618986
2008 CANu1, a novel nucleolar protein, accumulated on centromere in response to DNA damage. Genes to cells : devoted to molecular & cellular mechanisms 7 18547334
2005 Optimization of nitrogen for enhanced citric acid productivity by a 2-deoxy D-glucose resistant culture of Aspergillus niger NGd-280. Bioresource technology 7 15693171
2022 Vannella mustalahtiana sp. nov. (Amoebozoa, Vannellida) and rainbow trout nodular gill disease (NGD) in Russia. Diseases of aquatic organisms 6 35142296
2022 Artificial intelligence-assisted cryoEM structure of Bfr2-Lcp5 complex observed in the yeast small subunit processome. Communications biology 4 35650250
2011 Depletion of Neuroguidin/CANu1 sensitizes human osteosarcoma U2OS cells to doxorubicin. BMB reports 2 21266106
2025 Ptolemeba bulliensis Watson et al. 2014 (Amoebozoa, Tubulinea) From Freshwater NGD-Affected Rainbow Trout (Oncorhynchus mykiss Walbaum, 1792) Gills Tolerates Brackish Water Conditions. Journal of fish diseases 1 40207436