{"gene":"NUP54","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1991,"finding":"Nup54 (p54) forms a stable complex with p62 and p58 (Nup62 and Nup58) that is essential for nuclear pore function; depletion of this complex from nuclear reconstitution extracts abolishes nuclear transport, with a strict linear correlation between complex abundance and transport capacity.","method":"Co-immunoprecipitation, nuclear reconstitution depletion assay, gel filtration, nuclear transport assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution/depletion assay with quantitative transport readout, replicated by subsequent structural studies","pmids":["2050741"],"is_preprint":false},{"year":1994,"finding":"The p62–p58–p54 complex (Nup62/Nup58/Nup54) is released from the NPC as a discrete high-molecular-weight complex; p54 and p58 are not galactosylated in vitro, localizing this complex to the central channel region.","method":"Co-immunoprecipitation, detergent/high-salt extraction, in vitro galactosylation assay, immunogold electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods with structural localization","pmids":["8045926"],"is_preprint":false},{"year":2001,"finding":"The Nup62 complex (containing Nup54) in the central channel of the NPC provides a progressively higher-affinity binding site for importin-β cargo complexes relative to cytoplasmic Nup358, supporting a directional gradient model for nuclear import.","method":"Quantitative solid-phase binding assay, antibody inhibition of nuclear import","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative binding assay with functional antibody inhibition, single lab","pmids":["11266456"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, RNAi knockdown of the Nup54 fly homologue (but not most other FG nucleoporins) selectively impairs importin-α/β-mediated nuclear import without affecting CRM1-dependent export, demonstrating a selective role for Nup54 in the import pathway.","method":"RNA interference in Drosophila S2 cells, nuclear import/export assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — systematic RNAi screen across 30 nucleoporins with defined pathway-specific transport readouts","pmids":["17682050"],"is_preprint":false},{"year":2014,"finding":"The Nup62 complex (Nup62:Nup54:Nup58) exists in solution at a 1:1:1 stoichiometry, with Nup54 central and directly binding both Nup62 and Nup58 via conserved coiled-coil segments; at high concentrations the complex forms larger assemblies while maintaining this ratio. The same stoichiometry is conserved in the yeast Nsp1 complex.","method":"Gel filtration, analytical ultracentrifugation, in vitro reconstitution","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with two orthogonal hydrodynamic methods, evolutionary conservation validated","pmids":["24574455"],"is_preprint":false},{"year":2015,"finding":"The structured domain of Nup58 and the disordered FG domain of Nup54 are allosterically coupled: multivalent binding of importin-β Kapβ1 to the disordered domains of Nup58 stabilizes a neighboring structured domain associated with Nup54, shifting equilibria from homo-oligomers to hetero-oligomers, providing a quantitative framework for central channel constriction and dilation as a function of transport factor occupancy.","method":"Analysis of multiple equilibria (quantitative binding), crystallography, mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystallographic data combined with quantitative equilibrium analysis and mutagenesis in single rigorous study","pmids":["26046439"],"is_preprint":false},{"year":2015,"finding":"The ordered regions of Nup62, Nup54, and Nup58 form a dynamic triple complex in solution built from two sub-interactomes: a Nup54·Nup58 interaction and a Nup54·Nup62 triple helix ('finger'); crystal structure-deduced copy numbers suggest a 4:2:1 (Nup62:Nup54:Nup58) stoichiometry supporting a ring-cycle model for NPC channel dilation and constriction.","method":"Size-exclusion chromatography, analytical ultracentrifugation, X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures combined with multiple solution methods","pmids":["26025361"],"is_preprint":false},{"year":2017,"finding":"The FG domain of human Nup54 forms labile cross-β polymers detectable by chemical footprinting; mutations within the footprinted region block both polymerization and binding by the toxic PRn poly-dipeptide encoded by the C9orf72 repeat expansion, and 1,6-hexanediol melts these polymers in vitro, reversing PRn-mediated enhancement of nuclear pore permeability.","method":"Chemical footprinting, site-directed mutagenesis, in vitro polymerization assay, 1,6-hexanediol treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of polymer formation with mutagenesis and chemical perturbation, multiple orthogonal methods","pmids":["28069952"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, the Nup54 orthologue NPP-4 (along with NPP-1/Nup58 and NPP-11/Nup62) recruits PLK-1 to the nuclear pore complex via physical interaction with PLK-1's Polo-box domain, primed by Cdk1 and PLK-1 phosphorylation at multiple Polo-docking sites; this NPC-based recruitment is required for efficient nuclear envelope breakdown.","method":"Co-immunoprecipitation, genetic rescue, live-cell imaging, RNAi knockdown, phosphorylation site mapping","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic epistasis, and functional imaging in two species (C. elegans and human cells)","pmids":["29065307"],"is_preprint":false},{"year":2017,"finding":"Overexpression of NUP54 (along with NUP62) rescues the nuclear import defect of a TDP-43 NLS reporter caused by cytoplasmic poly-GA aggregates in C9orf72 ALS/FTLD, indicating that Nup54 functions in the importin-α/β-dependent nuclear import pathway.","method":"Fluorescence reporter rescue assay, overexpression in cell culture","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single rescue experiment without detailed mechanistic dissection","pmids":["28040728"],"is_preprint":false},{"year":2017,"finding":"The crystal structure of the Nup62 coiled-coil fragment reveals a parallel three-helix bundle that can form both homodimers/homotrimers and heterotrimers with Nup54 coiled-coil domain; comparative structural analysis demonstrates plasticity of the Nup62 coiled-coil enabling chain replacement to form diverse NPC assemblies.","method":"X-ray crystallography (2.4 Å), SEC-MALS, glutaraldehyde crosslinking","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with multiple solution-state validation methods","pmids":["28406021"],"is_preprint":false},{"year":2018,"finding":"Nup54 (with its partners Nup62 and Nup58) is required for homologous recombination (HR) repair of DNA double-strand breaks: Nup54 depletion epistasizes with Rad51 deficiency, decreases HR reporter activity, reduces HR-linked DNA synthesis foci and sister chromatid exchanges after ionizing radiation, and causes mitotic catastrophe and G2 arrest specifically in cells with replicated DNA.","method":"siRNA knockdown, HR reporter assay, epistasis analysis with Rad51, FACS cell-cycle analysis, chromosome aberration scoring","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays with defined genetic epistasis, clean KD phenotype","pmids":["29986057"],"is_preprint":false},{"year":2020,"finding":"In vivo FRET-based sensors show that the inner-ring nucleoporins Nup54, Nup58, and Nup62 undergo conformational changes when nucleocytoplasmic transport is perturbed, while Nups elsewhere in the NPC do not, indicating that the central channel undergoes dynamic conformational remodeling coupled to transport activity.","method":"Live-cell FRET imaging with rigidly conjugated mEGFP sensors, transport perturbation","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo conformational measurement with functional perturbation, single lab","pmids":["33346731"],"is_preprint":false},{"year":2021,"finding":"In Drosophila ovarian follicle cells, Nup54 and Nup58 are specifically required for piRNA biogenesis from the flamenco locus; loss of Nup54 or Nup58 compromises flamenco-dependent piRNA production without broadly disrupting nuclear transport, demonstrating a tissue-specific and locus-specific role for these channel nucleoporins in the piRNA pathway.","method":"RNAi knockdown in Drosophila ovaries, small RNA sequencing, genetic analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — systematic NPC subunit comparison with defined locus-specific piRNA sequencing readout","pmids":["33856346"],"is_preprint":false},{"year":2021,"finding":"Nup54 promotes CARM1 nuclear import in gastric cancer cells; once in the nucleus, CARM1 cooperates with TFEB to activate Notch2 transcription via H3R17me2 at the Notch2 promoter, and methylates N2ICD at R1786, R1838, and R2047, enhancing MAML1 binding and driving cell proliferation and tumor formation.","method":"Co-immunoprecipitation, nuclear fractionation, overexpression/knockdown, methylation assays, reporter assays, in vivo tumor xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple cell biological methods but mechanistic link between Nup54 and CARM1 import based primarily on co-IP and localization","pmids":["34725461"],"is_preprint":false},{"year":2021,"finding":"In Drosophila, Nup54 is required for correct wiring of eight adult brain neurons expressing pickpocket that mediate egg-laying, and viable Nup54 mutants prevent the sex-peptide-induced post-mating response including egg-laying and reduced receptivity; the Nup54 promoter is a hotspot for rapid evolution and promoter variants alter nucleo-cytoplasmic shuttling.","method":"Genetic mutagenesis screen, behavioral assays, neuroanatomical analysis, promoter reporter assay","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — genetic loss-of-function with specific neuronal and behavioral readouts, single lab","pmids":["34666772"],"is_preprint":false},{"year":2022,"finding":"Biallelic pathogenic variants in NUP54 clustered in the C-terminal region that interacts with NUP62 cause early-onset dystonia with striatal lesions; in silico and protein-biochemical studies confirmed these variants disrupt the NUP54–NUP62 interaction, establishing NUP54 as a disease gene for a neurodegenerative movement disorder.","method":"Patient sequencing, in silico structural modeling, protein-biochemical interaction studies","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 — human genetics with biochemical validation, but limited mechanistic depth beyond interaction disruption","pmids":["36333996"],"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 for correct spindle orientation and chromosome segregation.","method":"Mass spectrometry, co-immunoprecipitation, acetylation site mutagenesis, live-cell imaging, siRNA knockdown","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — PTM identification with mutagenesis and functional readout, though Nup54 role is as complex partner rather than direct acetylation substrate","pmids":["36190325"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, the Nup54 orthologue NPP-1 promotes perinuclear localization of the anti-silencing Argonaute CSR-1, placing Nup54 in the nuclear pore machinery required for piRNA-mediated gene silencing initiation.","method":"Sensitized piRNA reporter screen, fluorescence localization assay, RNAi knockdown in C. elegans","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — genetic screen with defined localization readout, single lab","pmids":["37210214"],"is_preprint":false}],"current_model":"NUP54 is a central channel nucleoporin that forms a stable 1:1:1 complex with NUP62 and NUP58 via conserved coiled-coil interactions, with NUP54 occupying the central scaffold position; this complex is essential for importin-α/β-mediated nuclear import, undergoes transport-coupled conformational changes, participates in allosteric gating of the NPC central channel by transport factors, contributes to homologous recombination repair of DNA double-strand breaks through epistatic interaction with RAD51, recruits PLK-1 for nuclear envelope breakdown in mitosis, and has tissue-specific roles in piRNA biogenesis and neuronal wiring, while pathogenic NUP54 variants disrupting its NUP62-binding C-terminal domain cause early-onset dystonia with striatal degeneration."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing that NUP54 is an essential subunit of a trimeric nucleoporin complex required for nuclear transport resolved the question of which NPC components constitute the functional transport machinery.","evidence":"Co-immunoprecipitation, depletion-reconstitution nuclear transport assay in Xenopus extracts","pmids":["2050741"],"confidence":"High","gaps":["Stoichiometry and direct contacts within the complex were undefined","Which specific transport pathway(s) the complex serves was unknown"]},{"year":1994,"claim":"Demonstrating that the NUP62–NUP54–NUP58 complex resides in the central channel of the NPC localized its function to the gated transport conduit rather than peripheral scaffolding structures.","evidence":"Detergent/salt extraction, immunogold EM, in vitro galactosylation assay","pmids":["8045926"],"confidence":"High","gaps":["Precise arrangement of subunits within the channel was unknown","Whether the complex undergoes conformational changes during transport was untested"]},{"year":2001,"claim":"Quantitative binding studies revealed that the NUP62 complex provides a higher-affinity importin-β binding site than cytoplasmic NUP358, supporting a gradient model for directional cargo translocation through the NPC.","evidence":"Solid-phase binding assay with purified nucleoporins, antibody inhibition of nuclear import","pmids":["11266456"],"confidence":"Medium","gaps":["Gradient model not tested with competing nucleoporins in an intact pore context","Affinity measurements were in vitro and may not reflect in vivo occupancy"]},{"year":2007,"claim":"Systematic RNAi screening showed NUP54 is selectively required for importin-α/β-mediated import but dispensable for CRM1-dependent export, establishing pathway specificity for the central channel complex.","evidence":"RNAi knockdown of 30 nucleoporins in Drosophila S2 cells with pathway-specific transport reporters","pmids":["17682050"],"confidence":"High","gaps":["Mechanism of selectivity for importin-α/β over CRM1 pathway was not resolved","Applicability to mammalian cells not directly tested in this study"]},{"year":2014,"claim":"Reconstitution and hydrodynamic analysis established the 1:1:1 stoichiometry of the complex with NUP54 as the central scaffold bridging NUP62 and NUP58, answering how the subunits are arranged.","evidence":"Gel filtration, analytical ultracentrifugation, in vitro reconstitution of human and yeast complexes","pmids":["24574455"],"confidence":"High","gaps":["Crystal structures of the full trimeric assembly were not yet available","Whether stoichiometry changes in situ within the NPC was unknown"]},{"year":2015,"claim":"Crystal structures and equilibrium analyses revealed that NUP54's disordered FG domains and NUP58's structured domains are allosterically coupled, with importin-β binding shifting oligomeric equilibria to provide a mechanism for transport-dependent channel gating.","evidence":"X-ray crystallography, quantitative multi-equilibrium analysis, mutagenesis; complementary structures of Nup54·Nup58 and Nup54·Nup62 subcomplexes","pmids":["26046439","26025361"],"confidence":"High","gaps":["Ring-cycle dilation/constriction model awaits validation in intact NPCs","Whether allosteric coupling operates on biologically relevant timescales in vivo was untested"]},{"year":2017,"claim":"Multiple studies converged to reveal NUP54's FG domain forms labile cross-β polymers that are disrupted by C9orf72 poly-dipeptides, its coiled-coil domain enables heterotrimeric chain exchange with NUP62, and the NPC-localized complex recruits PLK-1 for mitotic nuclear envelope breakdown — expanding NUP54's roles beyond steady-state transport.","evidence":"Chemical footprinting and mutagenesis of FG polymers; X-ray crystallography of NUP62 coiled-coil with SEC-MALS; Co-IP, genetic rescue, and live imaging of PLK-1 recruitment in C. elegans and human cells","pmids":["28069952","28406021","29065307"],"confidence":"High","gaps":["Whether cross-β polymers form in vivo within the NPC channel was not demonstrated","Structural basis for PLK-1 docking on NUP54 versus NUP62/NUP58 was not resolved"]},{"year":2018,"claim":"Demonstrating that NUP54 depletion impairs homologous recombination repair in epistasis with RAD51 established a transport-independent nuclear function for the central channel complex in genome maintenance.","evidence":"siRNA knockdown, HR reporter assay, epistasis with RAD51, sister chromatid exchange scoring, cell cycle analysis","pmids":["29986057"],"confidence":"High","gaps":["Whether NUP54 acts at DSB sites or through nuclear import of repair factors was not distinguished","Structural basis for the NUP54–RAD51 epistatic relationship is unknown"]},{"year":2020,"claim":"In vivo FRET sensors directly demonstrated that NUP54, NUP58, and NUP62 undergo conformational changes during active transport, validating the allosteric gating model in living cells.","evidence":"Live-cell FRET imaging with rigidly conjugated mEGFP sensors under transport perturbation","pmids":["33346731"],"confidence":"Medium","gaps":["FRET ensemble measurement does not resolve individual pore dynamics","Amplitude and kinetics of conformational change were not correlated with single-cargo transit events"]},{"year":2021,"claim":"Tissue-specific roles for NUP54 beyond bulk transport were established: NUP54 is required for piRNA biogenesis from the flamenco locus in Drosophila ovaries and for correct neuronal wiring underlying reproductive behavior, revealing specialized gene-regulatory functions.","evidence":"RNAi in Drosophila ovaries with small RNA sequencing; genetic mutagenesis with behavioral and neuroanatomical analysis","pmids":["33856346","34666772"],"confidence":"High","gaps":["Mechanism by which NUP54 specifically licenses flamenco piRNA production is unknown","Whether neuronal wiring defects reflect altered transport of specific cargoes or chromatin-level effects is unresolved"]},{"year":2022,"claim":"Pathogenic biallelic NUP54 variants disrupting the NUP62-binding C-terminal domain were identified as causal for early-onset dystonia with striatal degeneration, and mitotic dissolution of the complex by TIP60-mediated acetylation of NUP62 was characterized, linking post-translational regulation of complex integrity to cell division.","evidence":"Patient exome sequencing with biochemical validation of impaired NUP54–NUP62 interaction; mass spectrometry identification of NUP62 K432 acetylation with mutagenesis and live-cell imaging","pmids":["36333996","36190325"],"confidence":"Medium","gaps":["Neuronal cell-type vulnerability mechanism in dystonia is unexplained","Whether NUP54 itself is a direct acetylation or phosphorylation target regulating complex dissolution is unknown"]},{"year":2024,"claim":"NUP54 was placed in the piRNA pathway in C. elegans by showing its orthologue promotes perinuclear localization of the Argonaute CSR-1, extending the piRNA connection across phyla.","evidence":"Sensitized piRNA reporter screen, fluorescence localization assay, RNAi in C. elegans","pmids":["37210214"],"confidence":"Medium","gaps":["Whether NUP54 directly binds CSR-1 or acts indirectly through pore permeability is unknown","Conservation of this piRNA role in vertebrates is untested"]},{"year":null,"claim":"Key unresolved questions include how NUP54 distinguishes between importin-α/β and other transport receptors at the molecular level, whether its roles in HR repair and piRNA biogenesis are mechanistically linked to cargo selectivity or reflect transport-independent chromatin-proximal functions, and the structural basis for tissue-specific vulnerability in NUP54-associated dystonia.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of intact NUP62–NUP54–NUP58 complex within the NPC","Transport-independent versus transport-dependent mechanisms in HR repair are not distinguished","Neuronal cell-type specificity of NUP54 dystonia is mechanistically unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,4,6,10]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,3,5,9]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,8,12]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,3,5,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11]}],"complexes":["NUP62–NUP54–NUP58 complex (Nup62 complex)"],"partners":["NUP62","NUP58","KPNB1","PLK1","RAD51","CARM1"],"other_free_text":[]},"mechanistic_narrative":"NUP54 is a central channel nucleoporin that functions as the core scaffold of the NUP62–NUP54–NUP58 complex, directly binding both partners through conserved coiled-coil domains to form the principal permeability barrier and transport conduit of the nuclear pore complex [PMID:2050741, PMID:24574455, PMID:26025361]. The complex selectively facilitates importin-α/β-dependent nuclear import, provides progressively higher-affinity binding sites for importin-β that support directional cargo translocation, and undergoes allosteric conformational changes coupled to transport factor occupancy that gate the central channel between constricted and dilated states [PMID:11266456, PMID:17682050, PMID:26046439, PMID:33346731]. Beyond canonical transport, NUP54 participates in homologous recombination repair of DNA double-strand breaks in epistasis with RAD51, recruits PLK-1 via phosphorylation-primed Polo-box docking to drive nuclear envelope breakdown in mitosis, and has tissue-specific roles in piRNA biogenesis and neuronal wiring [PMID:29986057, PMID:29065307, PMID:33856346, PMID:34666772]. Biallelic pathogenic variants in the NUP62-binding C-terminal domain of NUP54 cause early-onset dystonia with striatal degeneration [PMID:36333996]."},"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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Mutations within the footprinted region blocked both polymerization and binding by PRn poly-dipeptides (encoded by C9orf72 repeat expansion). The aliphatic alcohol 1,6-hexanediol melted FG domain polymers in vitro and reversed PRn-mediated enhancement of nuclear pore permeability barrier, suggesting PRn toxicity results from locking Nup54 FG repeats in the polymerized state.\",\n      \"method\": \"Chemical footprinting, in vitro polymerization assay, mutagenesis, 1,6-hexanediol treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and chemical perturbation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28069952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of NUP54 (along with NUP62) rescues nuclear import of a TDP-43 NLS reporter that is blocked by cytoplasmic poly-GA aggregates in C9orf72 ALS/FTLD models, placing NUP54 in the importin-α/β-dependent nuclear import pathway.\",\n      \"method\": \"Rescue experiment with nucleoporin overexpression in cell-based nuclear import reporter assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional rescue experiment in cell model, single lab\",\n      \"pmids\": [\"28040728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, NPP-4 (ortholog of Nup54) is one of three central channel nucleoporins that recruit PLK-1 (Polo-like kinase 1) to nuclear pore complexes prior to nuclear envelope breakdown (NEBD). NPP-4 is primed at multiple Polo-docking sites by Cdk1 and PLK-1 itself, and physically interacts with the PLK-1 Polo-box domain (PBD) to anchor PLK-1 to the nuclear envelope, facilitating NEBD.\",\n      \"method\": \"Co-IP, epistasis genetics, phospho-site mapping, live imaging, RNAi knockdown in C. elegans and human cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic epistasis, functional rescue, replicated in both C. elegans and human cells\",\n      \"pmids\": [\"29065307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila S2 cells, Nup54 (fly homolog) is selectively required for importin α/β-mediated nuclear import but not CRM1-dependent export, as determined by RNAi knockdown and fluorescent import/export reporter assays.\",\n      \"method\": \"RNAi knockdown in Drosophila S2 cells with nuclear import/export reporters\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined pathway-specific phenotypic readout, single lab\",\n      \"pmids\": [\"17682050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nup54 is the central component of the Nup62 complex, directly binding both Nup62 and Nup58 via conserved coiled-coil segments in a 1:1:1 stoichiometry. At high concentrations, the complex forms larger assemblies while maintaining the ratio. Eliminating one binding partner leads to non-canonical stoichiometries. The same stoichiometry was found for the homologous yeast Nsp1 complex, indicating evolutionary conservation.\",\n      \"method\": \"In vitro gel filtration and analytical ultracentrifugation of recombinant proteins\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple biophysical methods, evolutionary conservation confirmed\",\n      \"pmids\": [\"24574455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Allosteric coupling exists between the structured domain of Nup58 and its neighboring disordered domain in interaction with Nup54 and transport factor Kapβ1. Multivalent interactions of Kapβ1 with disordered domains of Nup58 stabilize the neighboring structured domain associated with Nup54, shifting conformational equilibria from homo-oligomers to hetero-oligomers, providing a quantitative framework for constriction and dilation of the central NPC channel as a function of transport factor occupancy.\",\n      \"method\": \"Equilibrium binding analysis, crystallography, quantitative biophysical analysis of multiple equilibria\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystallographic data combined with quantitative binding analysis and mutagenesis, rigorous mechanistic framework\",\n      \"pmids\": [\"26046439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ordered regions of Nup54, Nup58, and Nup62 form a dynamic triple complex in solution, where Nup54 interacts with Nup58 (forming hetero-oligomers) and with Nup62 (forming a triple-helix 'finger' structure). These interactomes are consistent with a ring cycle model for dilation and constriction of the NPC central transport channel, with copy numbers of 128:64:32 for Nup62:Nup54:Nup58.\",\n      \"method\": \"Solution analysis (SEC, AUC, SAXS), prior crystal structure data\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple biophysical methods corroborated by crystallographic data\",\n      \"pmids\": [\"26025361\"],\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 exclusively from the flamenco locus, while knockdown of other NPC subunits has broader consequences. This demonstrates a tissue-specific, locus-specific role for Nup54 in transposon silencing via the piRNA pathway beyond its general nuclear transport function.\",\n      \"method\": \"Drosophila genetic knockdown, piRNA pathway reporter assays, small RNA sequencing\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined molecular phenotype, specificity controls with other Nups\",\n      \"pmids\": [\"33856346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup54 depletion by siRNA impairs homologous recombination (HR) DNA repair after ionizing radiation (IR), increases mitotic catastrophe, prolongs G2 arrest, and decreases HR-linked DNA synthesis foci and sister chromatid exchanges. Epistasis analysis showed Nup54 acts in the same pathway as Rad51 in HR repair.\",\n      \"method\": \"siRNA knockdown, HR reporter assays, epistasis with Rad51, BrdU incorporation, sister chromatid exchange assay, clonogenic survival\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (HR reporter, epistasis, SCE assay), defined pathway placement\",\n      \"pmids\": [\"29986057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup54 interacts with CARM1 and promotes its nuclear importation in gastric cancer cells. In the nucleus, CARM1 cooperates with TFEB to activate Notch2 transcription via H3R17 methylation of the Notch2 promoter. Loss-of-function and gain-of-function studies demonstrated Nup54-dependent CARM1 nuclear import is required for gastric cancer cell proliferation and tumor formation.\",\n      \"method\": \"Co-IP, nuclear fractionation, chromatin immunoprecipitation, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for interaction, functional consequences in cell and animal models, single lab\",\n      \"pmids\": [\"34725461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila, Nup54 loss-of-function mutants fail to lay eggs and show reduced receptivity after sex-peptide exposure. Nup54 directs correct wiring of eight adult brain pickpocket-expressing neurons required for egg-laying, placing Nup54 in the sex determination pathway controlling neuronal circuit formation.\",\n      \"method\": \"Drosophila genetics, viable mutant alleles, neuroanatomy (immunostaining of adult brain neurons), behavioral assays\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined neuronal and behavioral phenotype, single lab\",\n      \"pmids\": [\"34666772\"],\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 redistribution of Nup62 to the mitotic spindle for correct spindle orientation. This establishes that the Nup62-Nup54-Nup58 complex is a regulated assembly whose dissolution is required for accurate chromosome segregation.\",\n      \"method\": \"Co-IP, mass spectrometry, acetylation-mimetic and -deficient mutants, spindle orientation assays, chromosome segregation analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex dissolution shown by Co-IP with mutagenesis, functional mitotic phenotype, single lab\",\n      \"pmids\": [\"36190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The coiled-coil domain of Nup62 forms heterotrimeric complexes with Nup54 (and with Nup54-Nup58), as shown by crystal structures of Nup62(362-425) alone and in comparison to previously reported heterotrimeric structures with Nup54, demonstrating the structural basis for triple-helix bundle formation.\",\n      \"method\": \"X-ray crystallography (2.4 Å), SEC-MALS, glutaraldehyde crosslinking\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with solution validation by SEC-MALS and crosslinking\",\n      \"pmids\": [\"28406021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vivo fluorescence polarization sensors rigidly conjugated to Nup54 (and Nup58, Nup62) revealed conformational changes in the inner ring NPC components when nuclear transport is perturbed, while Nups elsewhere in the NPC showed no such changes, demonstrating that Nup54 is flexible and undergoes transport-dependent conformational changes in living cells.\",\n      \"method\": \"Live-cell fluorescence polarization imaging with rigidly conjugated mEGFP sensors\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo conformational measurement with functional perturbation, single lab\",\n      \"pmids\": [\"33346731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NUP54 was identified as a host factor required for influenza virus polymerase activity and virus replication, identified through yeast two-hybrid interaction with influenza polymerase subunits and confirmed by siRNA knockdown affecting transcriptional activity of the viral polymerase.\",\n      \"method\": \"Yeast two-hybrid, siRNA knockdown, viral polymerase transcription reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Y2H interaction confirmed with functional siRNA knockdown, single lab\",\n      \"pmids\": [\"21994455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic variants in NUP54 clustered in the C-terminal region that interacts with NUP62 cause early-onset dystonia with striatal lesions in humans. Protein-biochemical studies confirmed the variants disrupted NUP54-NUP62 interaction, establishing that the NUP54-NUP62 interaction is essential for human neurological function.\",\n      \"method\": \"Human genetics (whole-exome sequencing), in silico modeling, protein-biochemical interaction studies\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — human disease variants with biochemical validation of disrupted interaction, single study\",\n      \"pmids\": [\"36333996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, NPP-1/Nup54 (along with NPP-6/Nup160, NPP-7/Nup153, and FIB-1) promotes perinuclear localization of the anti-silencing CSR-1 Argonaute, placing Nup54 in the piRNA-mediated gene silencing pathway through regulation of Argonaute localization.\",\n      \"method\": \"C. elegans genetics, piRNA reporter assay, fluorescence microscopy of Argonaute localization\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular localization phenotype, single lab\",\n      \"pmids\": [\"37210214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP54 is a central channel nucleoporin that serves as a structural hub of the Nup62-Nup54-Nup58 complex (in 1:1:1 stoichiometry), where its coiled-coil domains mediate dynamic hetero- and homo-oligomeric interactions that undergo transport factor (Kapβ1)-dependent allosteric switching to dilate or constrict the NPC channel; its FG repeat domain forms cross-β polymers required for the selective permeability barrier; it is required for importin α/β-mediated nuclear import (but not CRM1-dependent export), recruits PLK-1 to the nuclear envelope via CDK1/PLK-1-primed docking sites to facilitate nuclear envelope breakdown in mitosis, participates in homologous recombination DNA repair in epistasis with Rad51, and has acquired tissue- and locus-specific roles including piRNA biogenesis at the flamenco locus and neuronal circuit wiring in Drosophila.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"Nup54 (p54) forms a stable complex with p62 and p58 (Nup62 and Nup58) that is essential for nuclear pore function; depletion of this complex from nuclear reconstitution extracts abolishes nuclear transport, with a strict linear correlation between complex abundance and transport capacity.\",\n      \"method\": \"Co-immunoprecipitation, nuclear reconstitution depletion assay, gel filtration, nuclear transport assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution/depletion assay with quantitative transport readout, replicated by subsequent structural studies\",\n      \"pmids\": [\"2050741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The p62–p58–p54 complex (Nup62/Nup58/Nup54) is released from the NPC as a discrete high-molecular-weight complex; p54 and p58 are not galactosylated in vitro, localizing this complex to the central channel region.\",\n      \"method\": \"Co-immunoprecipitation, detergent/high-salt extraction, in vitro galactosylation assay, immunogold electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods with structural localization\",\n      \"pmids\": [\"8045926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Nup62 complex (containing Nup54) in the central channel of the NPC provides a progressively higher-affinity binding site for importin-β cargo complexes relative to cytoplasmic Nup358, supporting a directional gradient model for nuclear import.\",\n      \"method\": \"Quantitative solid-phase binding assay, antibody inhibition of nuclear import\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative binding assay with functional antibody inhibition, single lab\",\n      \"pmids\": [\"11266456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, RNAi knockdown of the Nup54 fly homologue (but not most other FG nucleoporins) selectively impairs importin-α/β-mediated nuclear import without affecting CRM1-dependent export, demonstrating a selective role for Nup54 in the import pathway.\",\n      \"method\": \"RNA interference in Drosophila S2 cells, nuclear import/export assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic RNAi screen across 30 nucleoporins with defined pathway-specific transport readouts\",\n      \"pmids\": [\"17682050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Nup62 complex (Nup62:Nup54:Nup58) exists in solution at a 1:1:1 stoichiometry, with Nup54 central and directly binding both Nup62 and Nup58 via conserved coiled-coil segments; at high concentrations the complex forms larger assemblies while maintaining this ratio. The same stoichiometry is conserved in the yeast Nsp1 complex.\",\n      \"method\": \"Gel filtration, analytical ultracentrifugation, in vitro reconstitution\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with two orthogonal hydrodynamic methods, evolutionary conservation validated\",\n      \"pmids\": [\"24574455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The structured domain of Nup58 and the disordered FG domain of Nup54 are allosterically coupled: multivalent binding of importin-β Kapβ1 to the disordered domains of Nup58 stabilizes a neighboring structured domain associated with Nup54, shifting equilibria from homo-oligomers to hetero-oligomers, providing a quantitative framework for central channel constriction and dilation as a function of transport factor occupancy.\",\n      \"method\": \"Analysis of multiple equilibria (quantitative binding), crystallography, mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystallographic data combined with quantitative equilibrium analysis and mutagenesis in single rigorous study\",\n      \"pmids\": [\"26046439\"],\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 two sub-interactomes: a Nup54·Nup58 interaction and a Nup54·Nup62 triple helix ('finger'); crystal structure-deduced copy numbers suggest a 4:2:1 (Nup62:Nup54:Nup58) stoichiometry supporting a ring-cycle model for NPC channel dilation and constriction.\",\n      \"method\": \"Size-exclusion chromatography, analytical ultracentrifugation, X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures combined with multiple solution methods\",\n      \"pmids\": [\"26025361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The FG domain of human Nup54 forms labile cross-β polymers detectable by chemical footprinting; mutations within the footprinted region block both polymerization and binding by the toxic PRn poly-dipeptide encoded by the C9orf72 repeat expansion, and 1,6-hexanediol melts these polymers in vitro, reversing PRn-mediated enhancement of nuclear pore permeability.\",\n      \"method\": \"Chemical footprinting, site-directed mutagenesis, in vitro polymerization assay, 1,6-hexanediol treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of polymer formation with mutagenesis and chemical perturbation, multiple orthogonal methods\",\n      \"pmids\": [\"28069952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, the Nup54 orthologue NPP-4 (along with NPP-1/Nup58 and NPP-11/Nup62) recruits PLK-1 to the nuclear pore complex via physical interaction with PLK-1's Polo-box domain, primed by Cdk1 and PLK-1 phosphorylation at multiple Polo-docking sites; this NPC-based recruitment is required for efficient nuclear envelope breakdown.\",\n      \"method\": \"Co-immunoprecipitation, genetic rescue, live-cell imaging, RNAi knockdown, phosphorylation site mapping\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic epistasis, and functional imaging in two species (C. elegans and human cells)\",\n      \"pmids\": [\"29065307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of NUP54 (along with NUP62) rescues the nuclear import defect of a TDP-43 NLS reporter caused by cytoplasmic poly-GA aggregates in C9orf72 ALS/FTLD, indicating that Nup54 functions in the importin-α/β-dependent nuclear import pathway.\",\n      \"method\": \"Fluorescence reporter rescue assay, overexpression in cell culture\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single rescue experiment without detailed mechanistic dissection\",\n      \"pmids\": [\"28040728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The crystal structure of the Nup62 coiled-coil fragment reveals a parallel three-helix bundle that can form both homodimers/homotrimers and heterotrimers with Nup54 coiled-coil domain; comparative structural analysis demonstrates plasticity of the Nup62 coiled-coil enabling chain replacement to form diverse NPC assemblies.\",\n      \"method\": \"X-ray crystallography (2.4 Å), SEC-MALS, glutaraldehyde crosslinking\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with multiple solution-state validation methods\",\n      \"pmids\": [\"28406021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup54 (with its partners Nup62 and Nup58) is required for homologous recombination (HR) repair of DNA double-strand breaks: Nup54 depletion epistasizes with Rad51 deficiency, decreases HR reporter activity, reduces HR-linked DNA synthesis foci and sister chromatid exchanges after ionizing radiation, and causes mitotic catastrophe and G2 arrest specifically in cells with replicated DNA.\",\n      \"method\": \"siRNA knockdown, HR reporter assay, epistasis analysis with Rad51, FACS cell-cycle analysis, chromosome aberration scoring\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with defined genetic epistasis, clean KD phenotype\",\n      \"pmids\": [\"29986057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vivo FRET-based sensors show that the inner-ring nucleoporins Nup54, Nup58, and Nup62 undergo conformational changes when nucleocytoplasmic transport is perturbed, while Nups elsewhere in the NPC do not, indicating that the central channel undergoes dynamic conformational remodeling coupled to transport activity.\",\n      \"method\": \"Live-cell FRET imaging with rigidly conjugated mEGFP sensors, transport perturbation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo conformational measurement with functional perturbation, single lab\",\n      \"pmids\": [\"33346731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila ovarian follicle cells, Nup54 and Nup58 are specifically required for piRNA biogenesis from the flamenco locus; loss of Nup54 or Nup58 compromises flamenco-dependent piRNA production without broadly disrupting nuclear transport, demonstrating a tissue-specific and locus-specific role for these channel nucleoporins in the piRNA pathway.\",\n      \"method\": \"RNAi knockdown in Drosophila ovaries, small RNA sequencing, genetic analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic NPC subunit comparison with defined locus-specific piRNA sequencing readout\",\n      \"pmids\": [\"33856346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup54 promotes CARM1 nuclear import in gastric cancer cells; once in the nucleus, CARM1 cooperates with TFEB to activate Notch2 transcription via H3R17me2 at the Notch2 promoter, and methylates N2ICD at R1786, R1838, and R2047, enhancing MAML1 binding and driving cell proliferation and tumor formation.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, overexpression/knockdown, methylation assays, reporter assays, in vivo tumor xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple cell biological methods but mechanistic link between Nup54 and CARM1 import based primarily on co-IP and localization\",\n      \"pmids\": [\"34725461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila, Nup54 is required for correct wiring of eight adult brain neurons expressing pickpocket that mediate egg-laying, and viable Nup54 mutants prevent the sex-peptide-induced post-mating response including egg-laying and reduced receptivity; the Nup54 promoter is a hotspot for rapid evolution and promoter variants alter nucleo-cytoplasmic shuttling.\",\n      \"method\": \"Genetic mutagenesis screen, behavioral assays, neuroanatomical analysis, promoter reporter assay\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — genetic loss-of-function with specific neuronal and behavioral readouts, single lab\",\n      \"pmids\": [\"34666772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic pathogenic variants in NUP54 clustered in the C-terminal region that interacts with NUP62 cause early-onset dystonia with striatal lesions; in silico and protein-biochemical studies confirmed these variants disrupt the NUP54–NUP62 interaction, establishing NUP54 as a disease gene for a neurodegenerative movement disorder.\",\n      \"method\": \"Patient sequencing, in silico structural modeling, protein-biochemical interaction studies\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — human genetics with biochemical validation, but limited mechanistic depth beyond interaction disruption\",\n      \"pmids\": [\"36333996\"],\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 for correct spindle orientation and chromosome segregation.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, acetylation site mutagenesis, live-cell imaging, siRNA knockdown\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — PTM identification with mutagenesis and functional readout, though Nup54 role is as complex partner rather than direct acetylation substrate\",\n      \"pmids\": [\"36190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, the Nup54 orthologue NPP-1 promotes perinuclear localization of the anti-silencing Argonaute CSR-1, placing Nup54 in the nuclear pore machinery required for piRNA-mediated gene silencing initiation.\",\n      \"method\": \"Sensitized piRNA reporter screen, fluorescence localization assay, RNAi knockdown in C. elegans\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — genetic screen with defined localization readout, single lab\",\n      \"pmids\": [\"37210214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP54 is a central channel nucleoporin that forms a stable 1:1:1 complex with NUP62 and NUP58 via conserved coiled-coil interactions, with NUP54 occupying the central scaffold position; this complex is essential for importin-α/β-mediated nuclear import, undergoes transport-coupled conformational changes, participates in allosteric gating of the NPC central channel by transport factors, contributes to homologous recombination repair of DNA double-strand breaks through epistatic interaction with RAD51, recruits PLK-1 for nuclear envelope breakdown in mitosis, and has tissue-specific roles in piRNA biogenesis and neuronal wiring, while pathogenic NUP54 variants disrupting its NUP62-binding C-terminal domain cause early-onset dystonia with striatal degeneration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP54 is a central channel nucleoporin that functions as the structural hub of the Nup62–Nup54–Nup58 complex, mediating nuclear pore permeability, mitotic regulation, and specialized gene-regulatory processes. Its coiled-coil domains bind both Nup62 and Nup58 in 1:1:1 stoichiometry to form a triple-helix assembly whose conformational equilibria are allosterically modulated by the transport factor Kapβ1, providing a mechanism for dilation and constriction of the NPC central channel [PMID:24574455, PMID:26046439, PMID:26025361]. NUP54 is selectively required for importin-α/β-dependent nuclear import, participates in homologous recombination DNA repair in epistasis with Rad51, recruits PLK-1 to the nuclear envelope via CDK1-primed docking sites to facilitate nuclear envelope breakdown, and has tissue-specific roles in piRNA biogenesis at the flamenco locus and neuronal circuit wiring in Drosophila [PMID:17682050, PMID:29986057, PMID:29065307, PMID:33856346, PMID:34666772]. Biallelic variants in the NUP54 C-terminal region that disrupt NUP62 binding cause early-onset dystonia with striatal lesions in humans [PMID:36333996].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing pathway specificity: NUP54 was shown to be selectively required for importin-α/β-mediated nuclear import but dispensable for CRM1-dependent export, defining its transport function within the NPC.\",\n      \"evidence\": \"RNAi knockdown in Drosophila S2 cells with pathway-specific import/export reporters\",\n      \"pmids\": [\"17682050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of selectivity between import and export pathways not resolved\", \"Not tested in mammalian cells in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"NUP54 was implicated as a host factor for influenza virus replication through interaction with viral polymerase subunits, extending its role beyond endogenous nuclear transport.\",\n      \"evidence\": \"Yeast two-hybrid screen plus siRNA knockdown affecting viral polymerase activity\",\n      \"pmids\": [\"21994455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Y2H interaction lacks reciprocal biochemical validation\", \"Mechanism by which NUP54 supports viral polymerase activity undefined\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The structural basis for NUP54 as the central organizing subunit of the Nup62 complex was established: NUP54 directly binds both NUP62 and NUP58 via coiled-coil domains in 1:1:1 stoichiometry, and allosteric coupling between Kapβ1 binding and Nup58–Nup54 conformational switching provides a quantitative framework for NPC channel dilation and constriction.\",\n      \"evidence\": \"Recombinant reconstitution with SEC, AUC, SAXS, X-ray crystallography, and equilibrium binding analysis\",\n      \"pmids\": [\"24574455\", \"26046439\", \"26025361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry debated (128:64:32 vs 1:1:1 at NPC level)\", \"Full NPC context not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The FG repeat domain of NUP54 was shown to form labile cross-β polymers essential for the NPC permeability barrier, and disease-linked poly-dipeptides from C9orf72 expansion lock these polymers, providing a molecular mechanism for nucleocytoplasmic transport defects in ALS/FTLD.\",\n      \"evidence\": \"Chemical footprinting, in vitro polymerization, mutagenesis, and 1,6-hexanediol perturbation; NUP54 overexpression rescue of import defects in poly-GA aggregate model\",\n      \"pmids\": [\"28069952\", \"28040728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cross-β polymers form in the intact NPC in vivo not directly shown\", \"Overexpression rescue is indirect evidence for barrier function\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structures confirmed NUP54 forms heterotrimeric coiled-coil bundles with NUP62 (and NUP58), providing atomic-level detail for the triple-helix 'finger' structure within the central channel.\",\n      \"evidence\": \"X-ray crystallography at 2.4 Å with SEC-MALS and crosslinking validation\",\n      \"pmids\": [\"28406021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captures a static snapshot; dynamics of conformational switching not resolved crystallographically\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"NUP54 was established as a mitotic regulator: CDK1/PLK-1-primed phosphorylation creates Polo-box docking sites on NUP54 that recruit PLK-1 to the nuclear envelope, facilitating nuclear envelope breakdown.\",\n      \"evidence\": \"Co-IP, phospho-site mapping, epistasis genetics, RNAi, and live imaging in C. elegans and human cells\",\n      \"pmids\": [\"29065307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phospho-sites on human NUP54 not fully mapped\", \"Whether PLK-1 recruitment by NUP54 is rate-limiting for NEBD not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"NUP54 was shown to function in homologous recombination DNA repair, acting in the same genetic pathway as Rad51, revealing a non-transport role in genome maintenance.\",\n      \"evidence\": \"siRNA knockdown with HR reporter, epistasis analysis with Rad51, BrdU incorporation, sister chromatid exchange, and clonogenic survival assays\",\n      \"pmids\": [\"29986057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction with HR machinery not demonstrated\", \"Mechanism of NUP54 action in HR (e.g., Rad51 loading vs. nuclear import of repair factors) unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Live-cell fluorescence polarization directly demonstrated that NUP54 undergoes transport-dependent conformational changes within the NPC in vivo, validating the in vitro allosteric models.\",\n      \"evidence\": \"Fluorescence polarization sensors rigidly conjugated to NUP54 in living cells with transport perturbation\",\n      \"pmids\": [\"33346731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational changes not resolved at single-NPC level\", \"Cannot distinguish dilation from other structural rearrangements\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tissue-specific functions beyond general transport were established: NUP54 is required for piRNA biogenesis specifically from the flamenco locus in Drosophila follicle cells and for neuronal circuit wiring of pickpocket-expressing neurons controlling egg-laying behavior.\",\n      \"evidence\": \"Drosophila genetic knockdown/mutants, small RNA sequencing, neuroanatomical analysis, behavioral assays\",\n      \"pmids\": [\"33856346\", \"34666772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking NUP54 to flamenco-specific piRNA processing unknown\", \"Whether neuronal wiring defects reflect transport deficiency or NPC-independent scaffolding unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NUP54 was shown to promote CARM1 nuclear import in gastric cancer cells, coupling its transport function to epigenetic regulation of Notch2 transcription and tumor cell proliferation.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, chromatin immunoprecipitation, in vitro and in vivo tumor models\",\n      \"pmids\": [\"34725461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP54–CARM1 interaction is direct or mediated through the import machinery unclear\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Regulated dissolution of the NUP62–NUP54–NUP58 complex was demonstrated: TIP60-mediated acetylation of NUP62 at Lys432 dissociates the complex during mitotic entry, redirecting NUP62 to the spindle for proper chromosome segregation.\",\n      \"evidence\": \"Co-IP, mass spectrometry, acetylation-mimetic/deficient mutants, spindle orientation and segregation assays\",\n      \"pmids\": [\"36190325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP54 or NUP58 are also post-translationally modified during dissolution not tested\", \"In vivo acetylation dynamics not tracked in real time\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Biallelic NUP54 variants disrupting the NUP62-binding interface were identified as causative for early-onset dystonia with striatal lesions, establishing NUP54 as a Mendelian disease gene and demonstrating that the NUP54–NUP62 interaction is essential for human neurological function.\",\n      \"evidence\": \"Whole-exome sequencing in affected families, biochemical validation of disrupted NUP54–NUP62 interaction\",\n      \"pmids\": [\"36333996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small number of families; independent replication in larger cohorts needed\", \"Cellular pathology in patient neurons not characterized\", \"Whether dystonia results from transport defects, mitotic defects, or other NUP54 functions unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NUP54 was placed in the piRNA-mediated gene silencing pathway in C. elegans, where it promotes perinuclear localization of the CSR-1 Argonaute, extending its piRNA-related role to a second organism.\",\n      \"evidence\": \"C. elegans genetics, piRNA reporter assay, fluorescence microscopy of Argonaute localization\",\n      \"pmids\": [\"37210214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP54 directly anchors CSR-1 or acts through general NPC-mediated transport not distinguished\", \"Cross-species conservation of the piRNA-specific mechanism not established at the molecular level\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the molecular mechanism by which NUP54 selectively participates in HR repair (direct scaffolding vs. import of repair factors), how NUP54 achieves locus-specific piRNA biogenesis at flamenco, and the cellular pathology underlying NUP54-associated dystonia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for NUP54 FG domain polymers in the context of the intact NPC\", \"No reconstitution of NUP54's role in HR with purified components\", \"Mechanism connecting NUP54 variants to striatal neurodegeneration unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 6, 12]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [3, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 4, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 1, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 16]}\n    ],\n    \"complexes\": [\n      \"Nup62-Nup54-Nup58 complex\",\n      \"Nuclear pore complex (NPC)\"\n    ],\n    \"partners\": [\n      \"NUP62\",\n      \"NUP58\",\n      \"PLK1\",\n      \"CARM1\",\n      \"KPNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP54 is a central channel nucleoporin that functions as the core scaffold of the NUP62–NUP54–NUP58 complex, directly binding both partners through conserved coiled-coil domains to form the principal permeability barrier and transport conduit of the nuclear pore complex [PMID:2050741, PMID:24574455, PMID:26025361]. The complex selectively facilitates importin-α/β-dependent nuclear import, provides progressively higher-affinity binding sites for importin-β that support directional cargo translocation, and undergoes allosteric conformational changes coupled to transport factor occupancy that gate the central channel between constricted and dilated states [PMID:11266456, PMID:17682050, PMID:26046439, PMID:33346731]. Beyond canonical transport, NUP54 participates in homologous recombination repair of DNA double-strand breaks in epistasis with RAD51, recruits PLK-1 via phosphorylation-primed Polo-box docking to drive nuclear envelope breakdown in mitosis, and has tissue-specific roles in piRNA biogenesis and neuronal wiring [PMID:29986057, PMID:29065307, PMID:33856346, PMID:34666772]. Biallelic pathogenic variants in the NUP62-binding C-terminal domain of NUP54 cause early-onset dystonia with striatal degeneration [PMID:36333996].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that NUP54 is an essential subunit of a trimeric nucleoporin complex required for nuclear transport resolved the question of which NPC components constitute the functional transport machinery.\",\n      \"evidence\": \"Co-immunoprecipitation, depletion-reconstitution nuclear transport assay in Xenopus extracts\",\n      \"pmids\": [\"2050741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct contacts within the complex were undefined\", \"Which specific transport pathway(s) the complex serves was unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that the NUP62–NUP54–NUP58 complex resides in the central channel of the NPC localized its function to the gated transport conduit rather than peripheral scaffolding structures.\",\n      \"evidence\": \"Detergent/salt extraction, immunogold EM, in vitro galactosylation assay\",\n      \"pmids\": [\"8045926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise arrangement of subunits within the channel was unknown\", \"Whether the complex undergoes conformational changes during transport was untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Quantitative binding studies revealed that the NUP62 complex provides a higher-affinity importin-β binding site than cytoplasmic NUP358, supporting a gradient model for directional cargo translocation through the NPC.\",\n      \"evidence\": \"Solid-phase binding assay with purified nucleoporins, antibody inhibition of nuclear import\",\n      \"pmids\": [\"11266456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gradient model not tested with competing nucleoporins in an intact pore context\", \"Affinity measurements were in vitro and may not reflect in vivo occupancy\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Systematic RNAi screening showed NUP54 is selectively required for importin-α/β-mediated import but dispensable for CRM1-dependent export, establishing pathway specificity for the central channel complex.\",\n      \"evidence\": \"RNAi knockdown of 30 nucleoporins in Drosophila S2 cells with pathway-specific transport reporters\",\n      \"pmids\": [\"17682050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selectivity for importin-α/β over CRM1 pathway was not resolved\", \"Applicability to mammalian cells not directly tested in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstitution and hydrodynamic analysis established the 1:1:1 stoichiometry of the complex with NUP54 as the central scaffold bridging NUP62 and NUP58, answering how the subunits are arranged.\",\n      \"evidence\": \"Gel filtration, analytical ultracentrifugation, in vitro reconstitution of human and yeast complexes\",\n      \"pmids\": [\"24574455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structures of the full trimeric assembly were not yet available\", \"Whether stoichiometry changes in situ within the NPC was unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures and equilibrium analyses revealed that NUP54's disordered FG domains and NUP58's structured domains are allosterically coupled, with importin-β binding shifting oligomeric equilibria to provide a mechanism for transport-dependent channel gating.\",\n      \"evidence\": \"X-ray crystallography, quantitative multi-equilibrium analysis, mutagenesis; complementary structures of Nup54·Nup58 and Nup54·Nup62 subcomplexes\",\n      \"pmids\": [\"26046439\", \"26025361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ring-cycle dilation/constriction model awaits validation in intact NPCs\", \"Whether allosteric coupling operates on biologically relevant timescales in vivo was untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies converged to reveal NUP54's FG domain forms labile cross-β polymers that are disrupted by C9orf72 poly-dipeptides, its coiled-coil domain enables heterotrimeric chain exchange with NUP62, and the NPC-localized complex recruits PLK-1 for mitotic nuclear envelope breakdown — expanding NUP54's roles beyond steady-state transport.\",\n      \"evidence\": \"Chemical footprinting and mutagenesis of FG polymers; X-ray crystallography of NUP62 coiled-coil with SEC-MALS; Co-IP, genetic rescue, and live imaging of PLK-1 recruitment in C. elegans and human cells\",\n      \"pmids\": [\"28069952\", \"28406021\", \"29065307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cross-β polymers form in vivo within the NPC channel was not demonstrated\", \"Structural basis for PLK-1 docking on NUP54 versus NUP62/NUP58 was not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that NUP54 depletion impairs homologous recombination repair in epistasis with RAD51 established a transport-independent nuclear function for the central channel complex in genome maintenance.\",\n      \"evidence\": \"siRNA knockdown, HR reporter assay, epistasis with RAD51, sister chromatid exchange scoring, cell cycle analysis\",\n      \"pmids\": [\"29986057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NUP54 acts at DSB sites or through nuclear import of repair factors was not distinguished\", \"Structural basis for the NUP54–RAD51 epistatic relationship is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo FRET sensors directly demonstrated that NUP54, NUP58, and NUP62 undergo conformational changes during active transport, validating the allosteric gating model in living cells.\",\n      \"evidence\": \"Live-cell FRET imaging with rigidly conjugated mEGFP sensors under transport perturbation\",\n      \"pmids\": [\"33346731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FRET ensemble measurement does not resolve individual pore dynamics\", \"Amplitude and kinetics of conformational change were not correlated with single-cargo transit events\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tissue-specific roles for NUP54 beyond bulk transport were established: NUP54 is required for piRNA biogenesis from the flamenco locus in Drosophila ovaries and for correct neuronal wiring underlying reproductive behavior, revealing specialized gene-regulatory functions.\",\n      \"evidence\": \"RNAi in Drosophila ovaries with small RNA sequencing; genetic mutagenesis with behavioral and neuroanatomical analysis\",\n      \"pmids\": [\"33856346\", \"34666772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NUP54 specifically licenses flamenco piRNA production is unknown\", \"Whether neuronal wiring defects reflect altered transport of specific cargoes or chromatin-level effects is unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pathogenic biallelic NUP54 variants disrupting the NUP62-binding C-terminal domain were identified as causal for early-onset dystonia with striatal degeneration, and mitotic dissolution of the complex by TIP60-mediated acetylation of NUP62 was characterized, linking post-translational regulation of complex integrity to cell division.\",\n      \"evidence\": \"Patient exome sequencing with biochemical validation of impaired NUP54–NUP62 interaction; mass spectrometry identification of NUP62 K432 acetylation with mutagenesis and live-cell imaging\",\n      \"pmids\": [\"36333996\", \"36190325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal cell-type vulnerability mechanism in dystonia is unexplained\", \"Whether NUP54 itself is a direct acetylation or phosphorylation target regulating complex dissolution is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"NUP54 was placed in the piRNA pathway in C. elegans by showing its orthologue promotes perinuclear localization of the Argonaute CSR-1, extending the piRNA connection across phyla.\",\n      \"evidence\": \"Sensitized piRNA reporter screen, fluorescence localization assay, RNAi in C. elegans\",\n      \"pmids\": [\"37210214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP54 directly binds CSR-1 or acts indirectly through pore permeability is unknown\", \"Conservation of this piRNA role in vertebrates is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how NUP54 distinguishes between importin-α/β and other transport receptors at the molecular level, whether its roles in HR repair and piRNA biogenesis are mechanistically linked to cargo selectivity or reflect transport-independent chromatin-proximal functions, and the structural basis for tissue-specific vulnerability in NUP54-associated dystonia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of intact NUP62–NUP54–NUP58 complex within the NPC\", \"Transport-independent versus transport-dependent mechanisms in HR repair are not distinguished\", \"Neuronal cell-type specificity of NUP54 dystonia is mechanistically unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 4, 6, 10]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 3, 5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"NUP62–NUP54–NUP58 complex (Nup62 complex)\"\n    ],\n    \"partners\": [\n      \"NUP62\",\n      \"NUP58\",\n      \"KPNB1\",\n      \"PLK1\",\n      \"RAD51\",\n      \"CARM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}