{"gene":"NUP54","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2017,"finding":"The FG repeat domain of Nup54 forms labile cross-β polymers (characterized by chemical footprinting), and mutations within the footprinted region block both polymerization and binding by the toxic PRn poly-dipeptide encoded by C9orf72 repeat expansion. PRn binding locks FG repeats in the polymerized state, inhibiting nuclear import/export.","method":"Chemical footprinting of FG domain polymers, site-directed mutagenesis blocking polymerization, in vitro 1,6-hexanediol treatment to melt polymers","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of polymer formation, mutagenesis of active site, and chemical disruption with functional readout, single lab with multiple orthogonal methods","pmids":["28069952"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, channel nucleoporins NPP-4/Nup54 (along with NPP-1/Nup58 and NPP-11/Nup62) recruit PLK-1 to nuclear pore complexes prior to nuclear envelope breakdown (NEBD) via physical interaction between multiple Cdk1/PLK-1-primed Polo-docking sites and the PLK-1 Polo-box domain (PBD). This localization is required for efficient NEBD.","method":"Co-IP/pulldown of PLK-1 PBD with nucleoporins, genetic loss-of-function (RNAi) with NEBD phenotype, phosphorylation-site mutagenesis, live imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, genetic epistasis, functional phenotype (NEBD defect), replicated in both human cells and C. elegans with multiple orthogonal methods","pmids":["29065307"],"is_preprint":false},{"year":2015,"finding":"Nup54 is the central subunit of the Nup62 channel complex, directly binding both Nup62 and Nup58 via coiled-coil segments. The structured domain of Nup58 allosterically couples with its neighboring disordered domain in interaction with Nup54's disordered domain and transport factor Kapβ1; multivalent Kapβ1 interactions with disordered domains of Nup58 stabilize the structured domain associated with Nup54, shifting equilibria from homo-oligomers to hetero-oligomers, providing a mechanism for NPC central channel constriction/dilation.","method":"Crystallography, analytical ultracentrifugation, equilibrium binding analysis, in vitro reconstitution of complexes","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with quantitative equilibrium analysis and reconstitution, published in Cell with multiple orthogonal structural and biochemical methods","pmids":["26046439"],"is_preprint":false},{"year":2014,"finding":"The Nup62 complex (Nup62, Nup54, Nup58) has a 1:1:1 stoichiometry in solution, with Nup54 central and directly binding both Nup62 and Nup58 via conserved coiled-coil segments. This stoichiometry is conserved in the homologous yeast Nsp1 complex.","method":"Gel filtration chromatography, analytical ultracentrifugation, in vitro reconstitution","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with two orthogonal biophysical methods, evolutionary conservation demonstrated","pmids":["24574455"],"is_preprint":false},{"year":2015,"finding":"The ordered regions of Nup62, Nup54, and Nup58 form a dynamic 'triple complex' in solution built from characterized Nup54·Nup58 and Nup54·Nup62 interactomes. Nup54·Nup58 segments form inter-convertible hetero- and homo-oligomers proposed as 'mid-plane rings' for NPC channel dilation/constriction, while Nup54·Nup62 forms 1:2 triple-helix 'fingers' projecting from the ring.","method":"Solution analysis (SEC, AUC, SAXS), crystal structure analysis, in vitro reconstitution of sub-complexes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, crystal structure-derived model, multiple biophysical methods in single lab","pmids":["26025361"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, RNAi-mediated inactivation of Nup54 (fly homolog) selectively impairs importin α/β-mediated nuclear import but not CRM1-dependent export, identifying Nup54 FG nucleoporin as specifically required for the import pathway.","method":"RNAi knockdown in Drosophila S2 cells, nuclear import/export reporter assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi knockdown with defined pathway-specific phenotype, Drosophila ortholog study, single lab","pmids":["17682050"],"is_preprint":false},{"year":2018,"finding":"Nup54 (along with its complex partners Nup62 and Nup58) is required for homologous recombination (HR) repair. Nup54 depletion decreased HR repair activity (measured by specific reporters), reduced HR-linked DNA synthesis foci and sister chromatid exchanges after ionizing radiation, and increased chromosome aberrations. Nup54 is epistatic with HR factor Rad51, and its loss caused mitotic catastrophe and enhanced radiosensitivity specifically in cells with replicated DNA.","method":"siRNA knockdown, HR reporter assays, FACS cell cycle analysis, chromosome aberration analysis, epistasis analysis with Rad51, ionizing radiation survival assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (reporter, foci, SCE, epistasis), clean knockdown with specific mechanistic readouts, single lab","pmids":["29986057"],"is_preprint":false},{"year":2021,"finding":"In Drosophila ovarian follicle cells, Nup54 (along with Nup58) is specifically required for piRNA biogenesis from the flamenco locus, with loss of Nup54/Nup58 causing compromised piRNA production exclusively from this locus while knockdown of other NPC subunits has more widespread consequences, indicating a specialized role beyond general nuclear transport.","method":"RNAi knockdown in Drosophila ovary, small RNA sequencing, piRNA pathway reporter assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotype (locus-specific piRNA loss), single lab with sequencing validation","pmids":["33856346"],"is_preprint":false},{"year":2021,"finding":"In Drosophila, Nup54 loss-of-function mutations cause defective wiring of eight adult brain pickpocket-expressing neurons required for egg-laying, and reduce sensitivity to sex-peptide, indicating a role for Nup54 in neuronal circuit differentiation underlying the female post-mating response. Nup54 promoter variants alter nucleo-cytoplasmic shuttling.","method":"Forward genetic screen, viable mutant allele characterization, neuroanatomical analysis (brain neuron wiring), behavioral assays (egg-laying, sex-peptide sensitivity)","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific cellular and behavioral phenotype, single lab","pmids":["34666772"],"is_preprint":false},{"year":2021,"finding":"Nup54 promotes nuclear importation of the arginine methyltransferase CARM1; Nup54 was identified as a CARM1-interacting protein, and overexpression of Nup54 facilitates CARM1 nuclear import, which in turn activates Notch2 transcription and methylation in gastric cancer cells.","method":"Co-immunoprecipitation identifying Nup54-CARM1 interaction, nuclear fractionation showing CARM1 localization changes, functional proliferation and tumor formation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction, subcellular fractionation for localization, functional assays in cancer cells, single lab","pmids":["34725461"],"is_preprint":false},{"year":2017,"finding":"Expression of Nup54 (or Nup62) rescues nuclear import of a TDP-43 NLS reporter that is impaired by cytoplasmic poly-GA aggregates in C9orf72 ALS/FTLD, placing Nup54 in the importin-α/β-dependent nuclear import pathway as a downstream effector.","method":"Rescue/overexpression experiments in cell culture with fluorescent NLS reporter, nuclear import quantification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — rescue experiment with reporter assay establishing pathway placement, single lab, limited mechanistic depth","pmids":["28040728"],"is_preprint":false},{"year":2020,"finding":"In live cells, conformational changes of Nup54 (along with Nup58 and Nup62) within the NPC inner ring are detected when transport through the NPC is perturbed, while Nups elsewhere in the NPC show no such changes, indicating that these inner ring nucleoporins are flexible and undergo transport-state-dependent conformational changes.","method":"FRET-based conformational sensors with rigidly conjugated mEGFP on NPC proteins in live cells, transport perturbation assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell sensors with functional perturbation, single lab, novel method with appropriate controls","pmids":["33346731"],"is_preprint":false},{"year":2022,"finding":"TIP60-mediated acetylation of Nup62 at Lys432 dissolves the Nup62-Nup58-Nup54 complex during mitotic entry, promoting Nup62 redistribution to the mitotic spindle. This remodeling of the nucleoporin complex is required for correct spindle orientation and accurate chromosome segregation.","method":"Identification of TIP60 as acetyltransferase by biochemical assay, site-specific mutagenesis of Lys432, co-immunoprecipitation of Nup62-Nup58-Nup54 complex disruption, live imaging, spindle orientation and chromosome segregation assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM writer identified, mutagenesis, complex dissociation demonstrated, functional phenotype, single lab","pmids":["36190325"],"is_preprint":false},{"year":2022,"finding":"Biallelic (recessive) variants in NUP54 clustered in the C-terminal region that interacts with NUP62 cause early-onset dystonia with striatal lesions in humans, a phenotype similar to NUP62-related infantile striatonigral degeneration, establishing that the NUP54–NUP62 interaction is required for NPC function in the basal ganglia.","method":"Patient sequencing, in silico variant analysis, protein-biochemical studies confirming pathogenicity of variants affecting NUP62-interaction domain","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with protein-biochemical validation of variant effect, disease phenotype analogous to partner NUP62, single study","pmids":["36333996"],"is_preprint":false},{"year":2011,"finding":"NUP54 was identified as a host factor required for influenza virus polymerase replication/transcriptional activity in human cells, placing it in the nuclear transport function supporting viral RNA polymerase activity.","method":"Yeast two-hybrid screen for influenza polymerase interactors, siRNA knockdown validation of virus replication","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Y2H screen plus knockdown validation, pan-interactome study, limited mechanistic depth for NUP54 specifically","pmids":["21994455"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, nuclear pore component NPP-1/Nup54 promotes perinuclear localization of the anti-silencing CSR-1 Argonaute and is required for piRNA-mediated gene silencing initiation, linking NPC function to piRNA pathway regulation.","method":"Sensitized piRNA reporter screen, RNAi knockdown, fluorescence microscopy of Argonaute localization","journal":"Genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — screen-based identification, single knockdown with localization readout, limited mechanistic follow-up for Nup54 specifically","pmids":["37210214"],"is_preprint":false}],"current_model":"NUP54 is a central FG-nucleoporin of the nuclear pore complex (NPC) that occupies the core of the Nup62–Nup54–Nup58 channel subcomplex (in 1:1:1 stoichiometry) via coiled-coil interactions, with its structured domain allosterically coupling to its disordered FG-repeat region to mediate NPC channel dilation/constriction in response to transport factor (Kapβ1) occupancy; its FG repeats form cross-β polymers that provide the diffusion barrier and bind transport receptors for importin α/β-dependent nuclear import, and these polymers can be pathologically locked by C9orf72-derived PRn poly-dipeptides; beyond constitutive transport, Nup54 recruits PLK-1 to the NPC to drive nuclear envelope breakdown in mitosis, participates in homologous recombination DNA repair (epistatic with Rad51), supports locus-specific piRNA biogenesis in Drosophila follicle cells, promotes CARM1 nuclear import in gastric cancer, and directs neuronal circuit wiring for the female post-mating response in Drosophila, with loss-of-function variants in its NUP62-interaction domain causing early-onset dystonia with striatal lesions in humans."},"narrative":{"mechanistic_narrative":"NUP54 is a central FG-nucleoporin of the nuclear pore complex (NPC) that builds the diffusion barrier and transport conduit of the central channel and contributes to nuclear envelope dynamics during mitosis [PMID:26046439, PMID:29065307]. It is the central subunit of the Nup62 channel complex, assembling in 1:1:1 stoichiometry by directly binding both Nup62 and Nup58 through conserved coiled-coil segments, an architecture conserved in the yeast Nsp1 complex [PMID:24574455]. Within this assembly, the ordered Nup54·Nup58 and Nup54·Nup62 interactomes form dynamic, interconvertible hetero- and homo-oligomeric rings and triple-helix \"fingers,\" and multivalent engagement of the transport factor Kapβ1 shifts these equilibria to provide a mechanism for central-channel constriction and dilation [PMID:26025361, PMID:26046439]; consistent with this, these inner-ring nucleoporins undergo transport-state-dependent conformational changes in live cells [PMID:33346731]. The disordered FG-repeat region of Nup54 forms labile cross-β polymers required for the import barrier, and Nup54 is specifically required for importin α/β-dependent nuclear import [PMID:28069952, PMID:17682050]. These FG polymers are pathologically locked by C9orf72-derived PRn poly-dipeptides, inhibiting nucleocytoplasmic transport, while restoring Nup54 rescues import defects caused by C9orf72 poly-GA aggregates [PMID:28069952, PMID:28040728]. Beyond constitutive transport, Nup54 recruits PLK-1 to the NPC via Polo-docking sites to drive efficient nuclear envelope breakdown, and the complex is remodeled at mitotic entry by TIP60-mediated Nup62 acetylation to enable correct spindle orientation and chromosome segregation [PMID:29065307, PMID:36190325]. Nup54 also functions in homologous-recombination DNA repair epistatically with Rad51 [PMID:29986057], supports locus-specific piRNA biogenesis [PMID:33856346], and promotes nuclear import of the methyltransferase CARM1 in gastric cancer [PMID:34725461]. Biallelic variants clustered in the NUP62-interaction region cause early-onset dystonia with striatal lesions, establishing that the NUP54–NUP62 interaction is essential for NPC function in the basal ganglia [PMID:36333996].","teleology":[{"year":2007,"claim":"Established that Nup54 is not a generic channel filler but is selectively required for one directionality of transport, distinguishing its role in import from export.","evidence":"RNAi knockdown in Drosophila S2 cells with import/export reporter assays","pmids":["17682050"],"confidence":"Medium","gaps":["Does not define which FG segment mediates importin α/β selectivity","Drosophila ortholog; human pathway specificity not directly tested"]},{"year":2011,"claim":"Placed NUP54 among host factors supporting influenza polymerase activity, hinting that pathogens co-opt its transport function.","evidence":"Yeast two-hybrid screen for polymerase interactors plus siRNA replication validation","pmids":["21994455"],"confidence":"Low","gaps":["Single Y2H screen plus knockdown; no direct binding or mechanism for NUP54 specifically","Does not distinguish a specific interaction from a general transport requirement"]},{"year":2014,"claim":"Defined the stoichiometric architecture of the channel complex, showing Nup54 is the central organizing subunit bridging Nup62 and Nup58.","evidence":"In vitro reconstitution with gel filtration and analytical ultracentrifugation; conservation to yeast Nsp1","pmids":["24574455"],"confidence":"High","gaps":["Stoichiometry shown in solution, not within the assembled NPC","Does not address FG-region behavior"]},{"year":2015,"claim":"Resolved how the ordered and disordered segments couple, providing a molecular mechanism for channel dilation/constriction via Kapβ1-driven oligomer equilibria.","evidence":"Crystallography, AUC, SAXS and equilibrium binding analysis of reconstituted sub-complexes","pmids":["26046439","26025361"],"confidence":"High","gaps":["Allosteric model derived from in vitro equilibria, not direct NPC measurement","Does not capture FG-polymer contribution to gating"]},{"year":2017,"claim":"Showed that the Nup54 FG region forms labile cross-β polymers that constitute the diffusion barrier and become a target locked by C9orf72 PRn poly-dipeptides.","evidence":"Chemical footprinting, polymerization-blocking mutagenesis, and 1,6-hexanediol melting with functional transport readout","pmids":["28069952"],"confidence":"High","gaps":["Polymer state characterized in vitro; in-NPC polymer geometry unknown","Stoichiometry of PRn binding to FG repeats not quantified"]},{"year":2017,"claim":"Extended Nup54 function beyond steady-state transport by showing it recruits PLK-1 to the NPC to drive nuclear envelope breakdown at mitosis.","evidence":"PLK-1 PBD pulldowns, phospho-site mutagenesis, RNAi loss-of-function with NEBD live imaging in C. elegans","pmids":["29065307"],"confidence":"High","gaps":["Direct Nup54-PLK1 contact vs complex-level recruitment not fully separated","Human NEBD relevance shown but mechanism mapped chiefly in C. elegans"]},{"year":2017,"claim":"Linked Nup54 abundance to rescue of import defects in C9orf72 disease models, placing it as a downstream effector in the importin α/β pathway.","evidence":"Overexpression rescue of a TDP-43 NLS reporter against poly-GA aggregates in cell culture","pmids":["28040728"],"confidence":"Medium","gaps":["Rescue may reflect general transport buffering rather than specific repair of NUP54 function","Limited mechanistic depth"]},{"year":2018,"claim":"Revealed a non-transport role for Nup54 in homologous recombination, with loss causing radiosensitivity and mitotic catastrophe in replicated cells.","evidence":"siRNA knockdown, HR reporters, SCE and chromosome aberration analysis, Rad51 epistasis, IR survival","pmids":["29986057"],"confidence":"High","gaps":["Whether Nup54 acts at the pore or at repair sites is unresolved","Direct repair-factor contacts not identified"]},{"year":2020,"claim":"Demonstrated in living cells that inner-ring Nup54 physically changes conformation in response to transport state, validating the gating model.","evidence":"FRET conformational sensors with transport perturbation in live cells","pmids":["33346731"],"confidence":"Medium","gaps":["Conformational change not mapped to specific structural transitions","Causal link to dilation/constriction inferred"]},{"year":2021,"claim":"Uncovered specialized, non-canonical roles: locus-specific piRNA biogenesis, neuronal circuit wiring, and oncogenic CARM1 nuclear import.","evidence":"Drosophila RNAi/small-RNA-seq, forward-genetic mutant and behavioral analysis, and Co-IP/fractionation with cancer functional assays","pmids":["33856346","34666772","34725461"],"confidence":"Medium","gaps":["How a transport channel achieves locus-specific piRNA selectivity is unexplained","CARM1 interaction rests on single-lab Co-IP and fractionation"]},{"year":2022,"claim":"Showed the channel complex is actively remodeled at mitosis by TIP60 acetylation of Nup62, coupling Nup54 complex disassembly to spindle orientation and chromosome segregation.","evidence":"Acetyltransferase assay, Lys432 mutagenesis, Co-IP of complex dissociation, live imaging of spindle/segregation","pmids":["36190325"],"confidence":"Medium","gaps":["Direct functional consequence for Nup54 vs Nup62 redistribution not separated","Whether Nup54 itself is post-translationally regulated unknown"]},{"year":2022,"claim":"Established human disease causation, tying biallelic NUP54 variants in the NUP62-interaction domain to early-onset dystonia with striatal lesions.","evidence":"Patient sequencing with in silico and protein-biochemical validation of variant effects on the NUP62 interface","pmids":["36333996"],"confidence":"Medium","gaps":["Tissue-specific basis for basal ganglia vulnerability unknown","Single study; functional disease model not yet established"]},{"year":null,"claim":"How Nup54's structured channel architecture, its FG-polymer barrier, and its diverse moonlighting roles (HR repair, piRNA biogenesis, mitotic signaling) are mechanistically integrated within the assembled NPC remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the intact channel including FG polymers in situ","No unifying model connecting transport-independent roles to NPC architecture"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,2,11]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,5,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7]}],"complexes":["Nup62-Nup54-Nup58 channel complex"],"partners":["NUP62","NUP58","KAPΒ1","PLK-1","CARM1","RAD51"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z3B4","full_name":"Nucleoporin p54","aliases":["54 kDa nucleoporin"],"length_aa":507,"mass_kda":55.4,"function":"Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q7Z3B4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP54","classification":"Common Essential","n_dependent_lines":1007,"n_total_lines":1208,"dependency_fraction":0.8336092715231788},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CHMP7","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"XPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP54","total_profiled":1310},"omim":[{"mim_id":"620427","title":"DYSTONIA 37, EARLY-ONSET, WITH STRIATAL LESIONS; DYT37","url":"https://www.omim.org/entry/620427"},{"mim_id":"607615","title":"NUCLEOPORIN, 58-KD; NUP58","url":"https://www.omim.org/entry/607615"},{"mim_id":"607607","title":"NUCLEOPORIN, 54-KD; NUP54","url":"https://www.omim.org/entry/607607"},{"mim_id":"605815","title":"NUCLEOPORIN, 62-KD; NUP62","url":"https://www.omim.org/entry/605815"},{"mim_id":"271930","title":"STRIATONIGRAL DEGENERATION, INFANTILE; SNDI","url":"https://www.omim.org/entry/271930"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP54"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q7Z3B4","domains":[{"cath_id":"-","chopping":"114-173","consensus_level":"high","plddt":83.7392,"start":114,"end":173},{"cath_id":"3.30.70.3310","chopping":"176-347","consensus_level":"medium","plddt":91.4217,"start":176,"end":347}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3B4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3B4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3B4-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP54","jax_strain_url":"https://www.jax.org/strain/search?query=NUP54"},"sequence":{"accession":"Q7Z3B4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z3B4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z3B4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3B4"}},"corpus_meta":[{"pmid":"28069952","id":"PMC_28069952","title":"Toxic 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repeat domain of Nup54 forms labile cross-β polymers (characterized by chemical footprinting), and mutations within the footprinted region block both polymerization and binding by the toxic PRn poly-dipeptide encoded by C9orf72 repeat expansion. PRn binding locks FG repeats in the polymerized state, inhibiting nuclear import/export.\",\n      \"method\": \"Chemical footprinting of FG domain polymers, site-directed mutagenesis blocking polymerization, in vitro 1,6-hexanediol treatment to melt polymers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of polymer formation, mutagenesis of active site, and chemical disruption with functional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28069952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, channel nucleoporins NPP-4/Nup54 (along with NPP-1/Nup58 and NPP-11/Nup62) recruit PLK-1 to nuclear pore complexes prior to nuclear envelope breakdown (NEBD) via physical interaction between multiple Cdk1/PLK-1-primed Polo-docking sites and the PLK-1 Polo-box domain (PBD). This localization is required for efficient NEBD.\",\n      \"method\": \"Co-IP/pulldown of PLK-1 PBD with nucleoporins, genetic loss-of-function (RNAi) with NEBD phenotype, phosphorylation-site mutagenesis, live imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, genetic epistasis, functional phenotype (NEBD defect), replicated in both human cells and C. elegans with multiple orthogonal methods\",\n      \"pmids\": [\"29065307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nup54 is the central subunit of the Nup62 channel complex, directly binding both Nup62 and Nup58 via coiled-coil segments. The structured domain of Nup58 allosterically couples with its neighboring disordered domain in interaction with Nup54's disordered domain and transport factor Kapβ1; multivalent Kapβ1 interactions with disordered domains of Nup58 stabilize the structured domain associated with Nup54, shifting equilibria from homo-oligomers to hetero-oligomers, providing a mechanism for NPC central channel constriction/dilation.\",\n      \"method\": \"Crystallography, analytical ultracentrifugation, equilibrium binding analysis, in vitro reconstitution of complexes\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures combined with quantitative equilibrium analysis and reconstitution, published in Cell with multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"26046439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Nup62 complex (Nup62, Nup54, Nup58) has a 1:1:1 stoichiometry in solution, with Nup54 central and directly binding both Nup62 and Nup58 via conserved coiled-coil segments. This stoichiometry is conserved in the homologous yeast Nsp1 complex.\",\n      \"method\": \"Gel filtration chromatography, analytical ultracentrifugation, in vitro reconstitution\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with two orthogonal biophysical methods, evolutionary conservation demonstrated\",\n      \"pmids\": [\"24574455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ordered regions of Nup62, Nup54, and Nup58 form a dynamic 'triple complex' in solution built from characterized Nup54·Nup58 and Nup54·Nup62 interactomes. Nup54·Nup58 segments form inter-convertible hetero- and homo-oligomers proposed as 'mid-plane rings' for NPC channel dilation/constriction, while Nup54·Nup62 forms 1:2 triple-helix 'fingers' projecting from the ring.\",\n      \"method\": \"Solution analysis (SEC, AUC, SAXS), crystal structure analysis, in vitro reconstitution of sub-complexes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, crystal structure-derived model, multiple biophysical methods in single lab\",\n      \"pmids\": [\"26025361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, RNAi-mediated inactivation of Nup54 (fly homolog) selectively impairs importin α/β-mediated nuclear import but not CRM1-dependent export, identifying Nup54 FG nucleoporin as specifically required for the import pathway.\",\n      \"method\": \"RNAi knockdown in Drosophila S2 cells, nuclear import/export reporter assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi knockdown with defined pathway-specific phenotype, Drosophila ortholog study, single lab\",\n      \"pmids\": [\"17682050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup54 (along with its complex partners Nup62 and Nup58) is required for homologous recombination (HR) repair. Nup54 depletion decreased HR repair activity (measured by specific reporters), reduced HR-linked DNA synthesis foci and sister chromatid exchanges after ionizing radiation, and increased chromosome aberrations. Nup54 is epistatic with HR factor Rad51, and its loss caused mitotic catastrophe and enhanced radiosensitivity specifically in cells with replicated DNA.\",\n      \"method\": \"siRNA knockdown, HR reporter assays, FACS cell cycle analysis, chromosome aberration analysis, epistasis analysis with Rad51, ionizing radiation survival assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (reporter, foci, SCE, epistasis), clean knockdown with specific mechanistic readouts, single lab\",\n      \"pmids\": [\"29986057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila ovarian follicle cells, Nup54 (along with Nup58) is specifically required for piRNA biogenesis from the flamenco locus, with loss of Nup54/Nup58 causing compromised piRNA production exclusively from this locus while knockdown of other NPC subunits has more widespread consequences, indicating a specialized role beyond general nuclear transport.\",\n      \"method\": \"RNAi knockdown in Drosophila ovary, small RNA sequencing, piRNA pathway reporter assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotype (locus-specific piRNA loss), single lab with sequencing validation\",\n      \"pmids\": [\"33856346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila, Nup54 loss-of-function mutations cause defective wiring of eight adult brain pickpocket-expressing neurons required for egg-laying, and reduce sensitivity to sex-peptide, indicating a role for Nup54 in neuronal circuit differentiation underlying the female post-mating response. Nup54 promoter variants alter nucleo-cytoplasmic shuttling.\",\n      \"method\": \"Forward genetic screen, viable mutant allele characterization, neuroanatomical analysis (brain neuron wiring), behavioral assays (egg-laying, sex-peptide sensitivity)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific cellular and behavioral phenotype, single lab\",\n      \"pmids\": [\"34666772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup54 promotes nuclear importation of the arginine methyltransferase CARM1; Nup54 was identified as a CARM1-interacting protein, and overexpression of Nup54 facilitates CARM1 nuclear import, which in turn activates Notch2 transcription and methylation in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation identifying Nup54-CARM1 interaction, nuclear fractionation showing CARM1 localization changes, functional proliferation and tumor formation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction, subcellular fractionation for localization, functional assays in cancer cells, single lab\",\n      \"pmids\": [\"34725461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Expression of Nup54 (or Nup62) rescues nuclear import of a TDP-43 NLS reporter that is impaired by cytoplasmic poly-GA aggregates in C9orf72 ALS/FTLD, placing Nup54 in the importin-α/β-dependent nuclear import pathway as a downstream effector.\",\n      \"method\": \"Rescue/overexpression experiments in cell culture with fluorescent NLS reporter, nuclear import quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — rescue experiment with reporter assay establishing pathway placement, single lab, limited mechanistic depth\",\n      \"pmids\": [\"28040728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In live cells, conformational changes of Nup54 (along with Nup58 and Nup62) within the NPC inner ring are detected when transport through the NPC is perturbed, while Nups elsewhere in the NPC show no such changes, indicating that these inner ring nucleoporins are flexible and undergo transport-state-dependent conformational changes.\",\n      \"method\": \"FRET-based conformational sensors with rigidly conjugated mEGFP on NPC proteins in live cells, transport perturbation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell sensors with functional perturbation, single lab, novel method with appropriate controls\",\n      \"pmids\": [\"33346731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIP60-mediated acetylation of Nup62 at Lys432 dissolves the Nup62-Nup58-Nup54 complex during mitotic entry, promoting Nup62 redistribution to the mitotic spindle. This remodeling of the nucleoporin complex is required for correct spindle orientation and accurate chromosome segregation.\",\n      \"method\": \"Identification of TIP60 as acetyltransferase by biochemical assay, site-specific mutagenesis of Lys432, co-immunoprecipitation of Nup62-Nup58-Nup54 complex disruption, live imaging, spindle orientation and chromosome segregation assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM writer identified, mutagenesis, complex dissociation demonstrated, functional phenotype, single lab\",\n      \"pmids\": [\"36190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic (recessive) variants in NUP54 clustered in the C-terminal region that interacts with NUP62 cause early-onset dystonia with striatal lesions in humans, a phenotype similar to NUP62-related infantile striatonigral degeneration, establishing that the NUP54–NUP62 interaction is required for NPC function in the basal ganglia.\",\n      \"method\": \"Patient sequencing, in silico variant analysis, protein-biochemical studies confirming pathogenicity of variants affecting NUP62-interaction domain\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with protein-biochemical validation of variant effect, disease phenotype analogous to partner NUP62, single study\",\n      \"pmids\": [\"36333996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NUP54 was identified as a host factor required for influenza virus polymerase replication/transcriptional activity in human cells, placing it in the nuclear transport function supporting viral RNA polymerase activity.\",\n      \"method\": \"Yeast two-hybrid screen for influenza polymerase interactors, siRNA knockdown validation of virus replication\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Y2H screen plus knockdown validation, pan-interactome study, limited mechanistic depth for NUP54 specifically\",\n      \"pmids\": [\"21994455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, nuclear pore component NPP-1/Nup54 promotes perinuclear localization of the anti-silencing CSR-1 Argonaute and is required for piRNA-mediated gene silencing initiation, linking NPC function to piRNA pathway regulation.\",\n      \"method\": \"Sensitized piRNA reporter screen, RNAi knockdown, fluorescence microscopy of Argonaute localization\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — screen-based identification, single knockdown with localization readout, limited mechanistic follow-up for Nup54 specifically\",\n      \"pmids\": [\"37210214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP54 is a central FG-nucleoporin of the nuclear pore complex (NPC) that occupies the core of the Nup62–Nup54–Nup58 channel subcomplex (in 1:1:1 stoichiometry) via coiled-coil interactions, with its structured domain allosterically coupling to its disordered FG-repeat region to mediate NPC channel dilation/constriction in response to transport factor (Kapβ1) occupancy; its FG repeats form cross-β polymers that provide the diffusion barrier and bind transport receptors for importin α/β-dependent nuclear import, and these polymers can be pathologically locked by C9orf72-derived PRn poly-dipeptides; beyond constitutive transport, Nup54 recruits PLK-1 to the NPC to drive nuclear envelope breakdown in mitosis, participates in homologous recombination DNA repair (epistatic with Rad51), supports locus-specific piRNA biogenesis in Drosophila follicle cells, promotes CARM1 nuclear import in gastric cancer, and directs neuronal circuit wiring for the female post-mating response in Drosophila, with loss-of-function variants in its NUP62-interaction domain causing early-onset dystonia with striatal lesions in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP54 is a central FG-nucleoporin of the nuclear pore complex (NPC) that builds the diffusion barrier and transport conduit of the central channel and contributes to nuclear envelope dynamics during mitosis [#2, #1]. It is the central subunit of the Nup62 channel complex, assembling in 1:1:1 stoichiometry by directly binding both Nup62 and Nup58 through conserved coiled-coil segments, an architecture conserved in the yeast Nsp1 complex [#3]. Within this assembly, the ordered Nup54·Nup58 and Nup54·Nup62 interactomes form dynamic, interconvertible hetero- and homo-oligomeric rings and triple-helix \\\"fingers,\\\" and multivalent engagement of the transport factor Kapβ1 shifts these equilibria to provide a mechanism for central-channel constriction and dilation [#4, #2]; consistent with this, these inner-ring nucleoporins undergo transport-state-dependent conformational changes in live cells [#11]. The disordered FG-repeat region of Nup54 forms labile cross-β polymers required for the import barrier, and Nup54 is specifically required for importin α/β-dependent nuclear import [#0, #5]. These FG polymers are pathologically locked by C9orf72-derived PRn poly-dipeptides, inhibiting nucleocytoplasmic transport, while restoring Nup54 rescues import defects caused by C9orf72 poly-GA aggregates [#0, #10]. Beyond constitutive transport, Nup54 recruits PLK-1 to the NPC via Polo-docking sites to drive efficient nuclear envelope breakdown, and the complex is remodeled at mitotic entry by TIP60-mediated Nup62 acetylation to enable correct spindle orientation and chromosome segregation [#1, #12]. Nup54 also functions in homologous-recombination DNA repair epistatically with Rad51 [#6], supports locus-specific piRNA biogenesis [#7], and promotes nuclear import of the methyltransferase CARM1 in gastric cancer [#9]. Biallelic variants clustered in the NUP62-interaction region cause early-onset dystonia with striatal lesions, establishing that the NUP54–NUP62 interaction is essential for NPC function in the basal ganglia [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that Nup54 is not a generic channel filler but is selectively required for one directionality of transport, distinguishing its role in import from export.\",\n      \"evidence\": \"RNAi knockdown in Drosophila S2 cells with import/export reporter assays\",\n      \"pmids\": [\"17682050\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not define which FG segment mediates importin α/β selectivity\", \"Drosophila ortholog; human pathway specificity not directly tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed NUP54 among host factors supporting influenza polymerase activity, hinting that pathogens co-opt its transport function.\",\n      \"evidence\": \"Yeast two-hybrid screen for polymerase interactors plus siRNA replication validation\",\n      \"pmids\": [\"21994455\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single Y2H screen plus knockdown; no direct binding or mechanism for NUP54 specifically\", \"Does not distinguish a specific interaction from a general transport requirement\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the stoichiometric architecture of the channel complex, showing Nup54 is the central organizing subunit bridging Nup62 and Nup58.\",\n      \"evidence\": \"In vitro reconstitution with gel filtration and analytical ultracentrifugation; conservation to yeast Nsp1\",\n      \"pmids\": [\"24574455\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Stoichiometry shown in solution, not within the assembled NPC\", \"Does not address FG-region behavior\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how the ordered and disordered segments couple, providing a molecular mechanism for channel dilation/constriction via Kapβ1-driven oligomer equilibria.\",\n      \"evidence\": \"Crystallography, AUC, SAXS and equilibrium binding analysis of reconstituted sub-complexes\",\n      \"pmids\": [\"26046439\", \"26025361\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Allosteric model derived from in vitro equilibria, not direct NPC measurement\", \"Does not capture FG-polymer contribution to gating\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that the Nup54 FG region forms labile cross-β polymers that constitute the diffusion barrier and become a target locked by C9orf72 PRn poly-dipeptides.\",\n      \"evidence\": \"Chemical footprinting, polymerization-blocking mutagenesis, and 1,6-hexanediol melting with functional transport readout\",\n      \"pmids\": [\"28069952\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Polymer state characterized in vitro; in-NPC polymer geometry unknown\", \"Stoichiometry of PRn binding to FG repeats not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended Nup54 function beyond steady-state transport by showing it recruits PLK-1 to the NPC to drive nuclear envelope breakdown at mitosis.\",\n      \"evidence\": \"PLK-1 PBD pulldowns, phospho-site mutagenesis, RNAi loss-of-function with NEBD live imaging in C. elegans\",\n      \"pmids\": [\"29065307\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct Nup54-PLK1 contact vs complex-level recruitment not fully separated\", \"Human NEBD relevance shown but mechanism mapped chiefly in C. elegans\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked Nup54 abundance to rescue of import defects in C9orf72 disease models, placing it as a downstream effector in the importin α/β pathway.\",\n      \"evidence\": \"Overexpression rescue of a TDP-43 NLS reporter against poly-GA aggregates in cell culture\",\n      \"pmids\": [\"28040728\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Rescue may reflect general transport buffering rather than specific repair of NUP54 function\", \"Limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a non-transport role for Nup54 in homologous recombination, with loss causing radiosensitivity and mitotic catastrophe in replicated cells.\",\n      \"evidence\": \"siRNA knockdown, HR reporters, SCE and chromosome aberration analysis, Rad51 epistasis, IR survival\",\n      \"pmids\": [\"29986057\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether Nup54 acts at the pore or at repair sites is unresolved\", \"Direct repair-factor contacts not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated in living cells that inner-ring Nup54 physically changes conformation in response to transport state, validating the gating model.\",\n      \"evidence\": \"FRET conformational sensors with transport perturbation in live cells\",\n      \"pmids\": [\"33346731\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Conformational change not mapped to specific structural transitions\", \"Causal link to dilation/constriction inferred\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered specialized, non-canonical roles: locus-specific piRNA biogenesis, neuronal circuit wiring, and oncogenic CARM1 nuclear import.\",\n      \"evidence\": \"Drosophila RNAi/small-RNA-seq, forward-genetic mutant and behavioral analysis, and Co-IP/fractionation with cancer functional assays\",\n      \"pmids\": [\"33856346\", \"34666772\", \"34725461\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How a transport channel achieves locus-specific piRNA selectivity is unexplained\", \"CARM1 interaction rests on single-lab Co-IP and fractionation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed the channel complex is actively remodeled at mitosis by TIP60 acetylation of Nup62, coupling Nup54 complex disassembly to spindle orientation and chromosome segregation.\",\n      \"evidence\": \"Acetyltransferase assay, Lys432 mutagenesis, Co-IP of complex dissociation, live imaging of spindle/segregation\",\n      \"pmids\": [\"36190325\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct functional consequence for Nup54 vs Nup62 redistribution not separated\", \"Whether Nup54 itself is post-translationally regulated unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established human disease causation, tying biallelic NUP54 variants in the NUP62-interaction domain to early-onset dystonia with striatal lesions.\",\n      \"evidence\": \"Patient sequencing with in silico and protein-biochemical validation of variant effects on the NUP62 interface\",\n      \"pmids\": [\"36333996\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Tissue-specific basis for basal ganglia vulnerability unknown\", \"Single study; functional disease model not yet established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Nup54's structured channel architecture, its FG-polymer barrier, and its diverse moonlighting roles (HR repair, piRNA biogenesis, mitotic signaling) are mechanistically integrated within the assembled NPC remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structure of the intact channel including FG polymers in situ\", \"No unifying model connecting transport-independent roles to NPC architecture\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"Nup62-Nup54-Nup58 channel complex\"\n    ],\n    \"partners\": [\n      \"NUP62\",\n      \"NUP58\",\n      \"Kapβ1\",\n      \"PLK-1\",\n      \"CARM1\",\n      \"Rad51\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}