{"gene":"NUP133","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1995,"finding":"Disruption or mutation of yeast NUP133 (RAT3) causes temperature-dependent nuclear accumulation of poly(A)+ RNA and constitutive clustering of nuclear pore complexes into one or a few regions of the nuclear envelope, establishing Nup133 as a nucleoporin required for mRNA export and proper NPC distribution.","method":"Yeast genetics (temperature-sensitive mutants, gene disruption), fluorescent in situ hybridization for poly(A)+ RNA, indirect immunofluorescence, electron microscopy, epitope tagging and co-localization with NPC markers","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, independently confirmed by two labs in the same year (PMID 7626806 and 7862658)","pmids":["7626806","7862658"],"is_preprint":false},{"year":2001,"finding":"Vertebrate Nup133 and Nup160 were identified as novel nucleoporins that bind Nup98 and Nup153 (via pulldowns from Xenopus egg extracts), form a complex with Nup107, Nup96, and Sec13 (the Nup160 complex), are accessible on the basket side of the pore, and specific Nup133/Nup160 fragments block poly(A)+ RNA export but not protein import or export.","method":"Pulldown from Xenopus egg extracts, protein purification and sequencing, co-immunoprecipitation, immunofluorescence, in vivo transport assays (transfection of dominant-negative fragments)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pulldowns, complex reconstitution in extracts, functional in vivo transport assay with dominant-negative fragments","pmids":["11684705"],"is_preprint":false},{"year":2003,"finding":"The conserved Nup107-160 complex (containing Nup133) is critical for postmitotic NPC assembly: RNAi depletion of Nup133 or Nup107 in HeLa cells reduced nucleoporin levels and NPC density; immunodepletion of the entire complex from in vitro nuclear assembly reactions produced nuclei with a continuous NE but no NPCs, reversible only if the complex was added before closed NE formation.","method":"RNAi knockdown in HeLa cells, in vitro nuclear assembly assay with Xenopus egg extracts, immunodepletion, immunofluorescence, electron microscopy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — in vitro reconstitution/depletion combined with in vivo RNAi, multiple orthogonal readouts","pmids":["12705868"],"is_preprint":false},{"year":2004,"finding":"Human Nup133 contains two distinct domains: a C-terminal domain that mediates interaction with Nup107 (anchoring Nup133 to its subcomplex), and an N-terminal domain whose crystal structure reveals a seven-bladed beta-propeller with surface properties suggesting multiple protein interactions.","method":"Crystal structure determination of the N-terminal beta-propeller domain, deletion/domain mapping, co-immunoprecipitation to define Nup107-binding region","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with domain-function mapping","pmids":["15557116"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of the human Nup107–Nup133 C-terminal domain complex reveals that both proteins form elongated structures interacting tightly via a compact interface in tail-to-tail fashion; structure-guided mutagenesis confirms that Nup107 is the critical anchor positioning Nup133 at the periphery of the NPC.","method":"Crystal structure determination, structure-guided mutagenesis, functional interaction assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation","pmids":["18570875"],"is_preprint":false},{"year":2009,"finding":"Crystal structures of yNup170(979–1502) and hNup107(658–925)·hNup133(517–1156) reveal conserved domain arrangement and tertiary structure between Nup157/170 and Nup133, suggesting they descend from a common ancestral coatomer-like element (ACE); together with ACE1, these define the major alpha-helical building blocks of the NPC scaffold.","method":"Crystal structure determination, structural comparison, evolutionary analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures with structural validation","pmids":["19674973"],"is_preprint":false},{"year":2011,"finding":"The N-terminal domain of Nup133 (though largely dispensable for NPC assembly) is required for efficient anchoring of the dynein/dynactin complex to the nuclear envelope in prophase; Nup133 acts through an interaction network involving CENP-F and NudE/NudEL, and this molecular chain is critical for maintaining centrosome association with the NE at mitotic entry and contributes to bipolar spindle assembly.","method":"RNAi knockdown, dominant-negative domain expression, co-immunoprecipitation, live-cell imaging, immunofluorescence, genetic epistasis with RanBP2-BICD2 pathway","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, multiple dominant-negative constructs, live imaging, pathway epistasis","pmids":["21383080"],"is_preprint":false},{"year":2014,"finding":"Integrative structural modeling of yeast Nup133 using crystal structures, SAXS, negative-stain EM, and cross-linking mass spectrometry identified an ArfGAP1 lipid packing sensor (ALPS) motif in Nup133; mutational studies confirm this motif, suggesting Nup133's ALPS mediates membrane anchoring of the NPC in the nuclear envelope.","method":"Crystal structure determination (VpNup133), SAXS (18 constructs), negative-stain EM, cross-linking mass spectrometry, mutagenesis, integrative structural modeling","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal structural methods plus mutagenesis in a single study","pmids":["25139911"],"is_preprint":false},{"year":2018,"finding":"Loss of Nup133 in mouse embryonic stem cells specifically perturbs nuclear basket assembly: ~50% of NPCs lack Tpr, and Nup153 dynamics are altered; the central domain of Nup133 mediates its role in assembling Tpr and Nup153 into a properly configured nuclear basket, while Nup133 is dispensable for interphase and postmitotic NPC scaffold assembly in pluripotent mESCs.","method":"Null mutation in mice, single-pore detection by super-resolution microscopy, average NE-fluorescence intensity measurement, FRAP (Nup153 dynamics), domain mapping via rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic null combined with single-pore resolution imaging, FRAP, and domain rescue","pmids":["29791854"],"is_preprint":false},{"year":2018,"finding":"A homozygous NUP133 splicing mutation (c.3335-11T>A) causes Galloway-Mowat syndrome (microcephaly, brain anomalies, nephrotic syndrome); the mutation impairs NUP133–NUP107 interaction as shown by immunoprecipitation; nup133-knockdown zebrafish exhibit microcephaly, fewer neuronal cells, underdeveloped glomeruli, and podocyte foot process fusion, rescued by wild-type but not mutant human NUP133 mRNA.","method":"Whole exome sequencing, linkage analysis, immunoprecipitation (NUP133–NUP107 interaction), zebrafish morphant model, mRNA rescue experiments","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 — human genetics combined with functional zebrafish rescue experiments and biochemical interaction assay","pmids":["30427554"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of full-length yeast Nup84–Nup133 C-terminal domain complex and the Nup133 N-terminal domain (nanobody-bound) reveal high flexibility of this dimeric unit; the Nup133 NTD contains a structurally conserved ALPS motif confirmed by liposome interaction studies to mediate membrane binding.","method":"Cryo-EM/X-ray crystallography with nanobody-bound complexes, liposome interaction assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro liposome binding assay confirming ALPS function","pmids":["33247142"],"is_preprint":false},{"year":2020,"finding":"Nup133 protein level declines in male but not female mouse oligodendrocyte progenitor cells (OPCs) following hyperoxia; Nrf1 is identified as a direct downstream transcriptional target of Nup133, and Nup133 regulates mitochondrial function and oxidative stress response through Nrf1.","method":"Cell culture (primary OPCs), hyperoxia treatment, western blotting, siRNA knockdown, reporter assays for Nrf1 transcriptional regulation","journal":"Molecular and cellular pediatrics","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic follow-up, no direct binding assay between Nup133 and Nrf1","pmids":["32844334"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9-mediated NUP133 loss-of-function in human podocytes disrupts nuclear pore scaffold assembly, alters the podocyte-specific transcriptome, and impairs cellular protrusion generation; SRNS-related NUP133 point mutations show only mild defects but impair Y-complex protein interaction and reduce NUP133 protein levels, suggesting partial loss-of-function as the disease mechanism.","method":"CRISPR/Cas9 genome editing, RNA-seq transcriptome analysis, immunofluorescence (NPC assembly), co-immunoprecipitation (Y-complex interaction), cytoskeletal/protrusion assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with multiple readouts, but single lab","pmids":["35455939"],"is_preprint":false}],"current_model":"NUP133 is a scaffold nucleoporin that anchors to the NPC periphery via its C-terminal interaction with NUP107, contributes to NPC biogenesis and proper NPC distribution (preventing clustering), promotes mRNA export, assembles the nuclear basket (recruiting Tpr and Nup153) through its central domain, uses an N-terminal ALPS motif for membrane anchoring of the NPC, and — through its N-terminal domain — recruits dynein/dynactin to the nuclear envelope via a CENP-F/NudE/NudEL chain to tether centrosomes at mitotic entry; loss-of-function mutations cause Galloway-Mowat syndrome and steroid-resistant nephrotic syndrome."},"narrative":{"teleology":[{"year":1995,"claim":"The first functional characterization established that Nup133 is required for two fundamental NPC-associated processes—mRNA export and the even distribution of pores across the nuclear envelope—answering whether this nucleoporin has roles beyond structural scaffolding.","evidence":"Yeast gene disruption and temperature-sensitive mutants with poly(A)+ RNA FISH, immunofluorescence, and EM","pmids":["7626806","7862658"],"confidence":"High","gaps":["Mechanism of NPC clustering upon Nup133 loss not resolved","Direct versus indirect role in mRNA export undefined"]},{"year":2001,"claim":"Identification of vertebrate Nup133 as a subunit of a Nup107-containing complex (with Nup96 and Sec13) and demonstration that specific Nup133 fragments block poly(A)+ RNA export established the biochemical context of Nup133 within a larger NPC subcomplex.","evidence":"Pulldowns from Xenopus egg extracts, co-IP, dominant-negative fragment transport assays in vivo","pmids":["11684705"],"confidence":"High","gaps":["Stoichiometry and architectural position within the complex not determined","Binding interface between Nup133 and Nup107 not structurally resolved"]},{"year":2003,"claim":"Depletion experiments demonstrated that the Nup107-160 complex (including Nup133) is essential for postmitotic NPC assembly, and must be incorporated before nuclear envelope closure, resolving the temporal requirement for this subcomplex in pore biogenesis.","evidence":"RNAi in HeLa cells combined with in vitro nuclear assembly in Xenopus egg extracts, immunodepletion and EM","pmids":["12705868"],"confidence":"High","gaps":["Individual contribution of Nup133 versus other Y-complex subunits to assembly not separated","Mechanism by which the complex seeds NPC insertion into membranes unknown"]},{"year":2004,"claim":"Structural and biochemical dissection of human Nup133 revealed a two-domain architecture—an N-terminal β-propeller and a C-terminal region that directly binds Nup107—providing the first molecular framework for understanding how Nup133 is anchored to its subcomplex while presenting an interaction surface for additional partners.","evidence":"X-ray crystallography of the N-terminal β-propeller, domain deletions and co-IP","pmids":["15557116"],"confidence":"High","gaps":["Function of the N-terminal β-propeller surface unknown","Atomic details of the Nup107-binding interface not yet resolved"]},{"year":2008,"claim":"The crystal structure of the Nup107–Nup133 C-terminal complex revealed a tail-to-tail elongated interface and confirmed via mutagenesis that Nup107 is the critical anchor positioning Nup133 at the NPC periphery, resolving the architecture of this dimer.","evidence":"X-ray crystallography and structure-guided mutagenesis","pmids":["18570875"],"confidence":"High","gaps":["How the Nup107–Nup133 dimer integrates into the full Y-complex ring not structurally resolved","Conformational dynamics in vivo unknown"]},{"year":2009,"claim":"Structural comparison of Nup133 with Nup157/170 demonstrated that NPC scaffold nucleoporins share an ancestral coatomer-like element (ACE), establishing the evolutionary origin of the NPC scaffold from protocoatomer building blocks.","evidence":"Crystal structures and structural homology analysis of yeast Nup170 and human Nup107·Nup133","pmids":["19674973"],"confidence":"High","gaps":["Functional consequences of the ACE-fold conservation not tested directly"]},{"year":2011,"claim":"Discovery that the Nup133 N-terminal domain recruits dynein/dynactin to the nuclear envelope during prophase via a CENP-F–NudE/NudEL chain revealed a mitotic function for this nucleoporin in centrosome tethering and bipolar spindle assembly, independent of its NPC scaffolding role.","evidence":"RNAi, dominant-negative domains, co-IP, live-cell imaging, epistasis with the RanBP2–BICD2 pathway in HeLa cells","pmids":["21383080"],"confidence":"High","gaps":["Whether the ALPS motif and dynein-recruitment function overlap spatially on the N-terminal domain not resolved","Regulation of the Nup133–CENP-F interaction across the cell cycle unclear"]},{"year":2014,"claim":"Identification and validation of an ArfGAP1 lipid packing sensor (ALPS) motif within the Nup133 N-terminal domain resolved how the NPC is anchored to the curved pore membrane, providing a direct membrane-sensing mechanism for scaffold nucleoporins.","evidence":"Integrative structural modeling (SAXS, EM, crosslinking MS, crystallography), mutagenesis of ALPS motif","pmids":["25139911"],"confidence":"High","gaps":["Quantitative contribution of the ALPS motif to NPC stability in vivo not measured","Lipid specificity of the ALPS motif not characterized"]},{"year":2018,"claim":"Two parallel advances resolved: (1) Nup133's central domain specifically assembles the nuclear basket by recruiting Tpr and stabilizing Nup153, distinguishing basket assembly from scaffold assembly; and (2) a NUP133 splicing mutation causes Galloway-Mowat syndrome by disrupting NUP107 interaction, linking Nup133 loss-of-function to human neurodevelopmental and renal disease.","evidence":"Nup133-null mESCs with super-resolution microscopy and FRAP (basket assembly); human WES, co-IP, and zebrafish morphant rescue (disease)","pmids":["29791854","30427554"],"confidence":"High","gaps":["How the central domain contacts Tpr and Nup153 at the molecular level is unknown","Genotype-phenotype spectrum across different NUP133 mutations remains incomplete","Whether basket deficiency or general NPC dysfunction drives Galloway-Mowat pathology not distinguished"]},{"year":2022,"claim":"CRISPR knockout of NUP133 in human podocytes confirmed that NPC scaffold assembly, the podocyte transcriptome, and cellular protrusion formation all depend on NUP133, while disease-associated point mutations cause partial loss-of-function through reduced Y-complex interaction and lower protein levels.","evidence":"CRISPR/Cas9 KO and point-mutation knock-in in human podocytes, RNA-seq, co-IP, protrusion assays","pmids":["35455939"],"confidence":"Medium","gaps":["Results from a single lab; independent replication pending","Molecular basis for protrusion defects downstream of NPC disruption not determined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of Nup133's central-domain interaction with Tpr/Nup153 for basket assembly, the mechanistic relationship between NPC basket deficiency and Galloway-Mowat syndrome pathology, and how the three distinct functional surfaces (ALPS, dynein-recruitment, basket-assembly) are coordinately regulated across the cell cycle.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of Nup133–Tpr or Nup133–Nup153 interaction","Cell-cycle regulation of Nup133 N-terminal domain functions (ALPS vs dynein) unknown","Tissue-specific consequences of partial NUP133 loss not systematically studied"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,3,4,5,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,2,6,7,8,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,8]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,2,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,12]}],"complexes":["Nup107-160 complex (Y-complex)","Nuclear pore complex (NPC)"],"partners":["NUP107","NUP96","SEC13","NUP160","TPR","NUP153","CENPF","NUP98"],"other_free_text":[]},"mechanistic_narrative":"NUP133 is a scaffold nucleoporin of the Nup107-160 (Y-complex) that is essential for nuclear pore complex biogenesis, proper NPC distribution across the nuclear envelope, mRNA export, and nuclear basket assembly. Its C-terminal domain anchors to Nup107 in a tail-to-tail arrangement positioning Nup133 at the NPC periphery [PMID:18570875], while its N-terminal β-propeller contains an ALPS motif that mediates direct membrane binding to tether the NPC to the nuclear envelope [PMID:25139911, PMID:33247142]. Beyond interphase NPC function, the N-terminal domain recruits dynein/dynactin to the nuclear envelope during prophase via a CENP-F/NudE/NudEL chain, thereby maintaining centrosome–NE association at mitotic entry [PMID:21383080], and the central domain is required for assembling Tpr and Nup153 into the nuclear basket [PMID:29791854]. Homozygous loss-of-function mutations in NUP133 cause Galloway-Mowat syndrome featuring microcephaly, brain anomalies, and nephrotic syndrome [PMID:30427554]."},"prefetch_data":{"uniprot":{"accession":"Q8WUM0","full_name":"Nuclear pore complex protein Nup133","aliases":["133 kDa nucleoporin","Nucleoporin Nup133"],"length_aa":1156,"mass_kda":129.0,"function":"Involved in poly(A)+ RNA transport. Involved in nephrogenesis (PubMed:30179222)","subcellular_location":"Nucleus, nuclear pore complex; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q8WUM0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP133","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUP107","stoichiometry":10.0},{"gene":"NUP98","stoichiometry":10.0},{"gene":"CLIP1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RAB11A","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP133","total_profiled":1310},"omim":[{"mim_id":"621033","title":"NUP210-LIKE PROTEIN; NUP210L","url":"https://www.omim.org/entry/621033"},{"mim_id":"618349","title":"GALLOWAY-MOWAT SYNDROME 8; GAMOS8","url":"https://www.omim.org/entry/618349"},{"mim_id":"618348","title":"GALLOWAY-MOWAT SYNDROME 7; GAMOS7","url":"https://www.omim.org/entry/618348"},{"mim_id":"618177","title":"NEPHROTIC SYNDROME, TYPE 18; NPHS18","url":"https://www.omim.org/entry/618177"},{"mim_id":"616730","title":"NEPHROTIC SYNDROME, TYPE 11; NPHS11","url":"https://www.omim.org/entry/616730"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP133"},"hgnc":{"alias_symbol":["FLJ10814"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUM0","domains":[{"cath_id":"2.130.10.10","chopping":"71-252","consensus_level":"medium","plddt":83.6966,"start":71,"end":252},{"cath_id":"2.130.10.10","chopping":"280-444","consensus_level":"medium","plddt":90.0396,"start":280,"end":444},{"cath_id":"-","chopping":"634-854","consensus_level":"medium","plddt":84.4848,"start":634,"end":854},{"cath_id":"1.20.58.1380","chopping":"944-1027","consensus_level":"medium","plddt":88.654,"start":944,"end":1027},{"cath_id":"1.25.40.700","chopping":"1028-1155","consensus_level":"high","plddt":76.6481,"start":1028,"end":1155},{"cath_id":"1.20.272","chopping":"514-551_558-625","consensus_level":"medium","plddt":73.7049,"start":514,"end":625}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUM0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUM0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUM0-F1-predicted_aligned_error_v6.png","plddt_mean":78.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP133","jax_strain_url":"https://www.jax.org/strain/search?query=NUP133"},"sequence":{"accession":"Q8WUM0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUM0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUM0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUM0"}},"corpus_meta":[{"pmid":"11684705","id":"PMC_11684705","title":"Novel 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transport assay, immunofluorescence) in a single highly-cited study\",\n      \"pmids\": [\"11684705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast Nup133p (Rat3p) is a nuclear pore complex protein whose mutation or deletion causes temperature-dependent nuclear accumulation of poly(A)+ RNA and constitutive clustering of NPCs into one or a few regions of the nuclear envelope, establishing its role in mRNA export and NPC distribution.\",\n      \"method\": \"Temperature-sensitive mutant isolation, FISH for poly(A)+ RNA, indirect immunofluorescence, electron microscopy, gene disruption, epitope tagging and localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, FISH, EM, immunofluorescence), replicated by independent lab (PMID 7862658)\",\n      \"pmids\": [\"7626806\", \"7862658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Disruption of yeast NUP133 causes clustering of nuclear pore complexes, phenocopying NUP145 disruption, suggesting Nup133p functions in maintaining NPC position within the nuclear envelope.\",\n      \"method\": \"Gene disruption, cell fractionation co-enrichment with NPC fraction, electron microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic disruption with EM phenotype, independently replicated\",\n      \"pmids\": [\"7862658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human Nup133 contains two domains: a C-terminal domain that mediates interaction with Nup107 to anchor Nup133 within the NPC subcomplex, and an N-terminal seven-bladed beta-propeller domain whose crystal structure was solved, suggesting multiple protein interaction surfaces.\",\n      \"method\": \"Crystal structure determination of N-terminal domain, domain mapping experiments, interaction assays with Nup107\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with domain mapping and functional interaction studies\",\n      \"pmids\": [\"15557116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the human Nup107-Nup133 C-terminal domain complex shows both proteins form elongated structures that interact tightly via a compact tail-to-tail interface; structure-guided mutagenesis confirms Nup107 is the critical anchor for Nup133 to the NPC, positioning Nup133 at the NPC periphery.\",\n      \"method\": \"Crystal structure determination, structure-guided mutagenesis, binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis with functional validation\",\n      \"pmids\": [\"18570875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structures of yNup170 and hNup107-hNup133 reveal that Nup157/170 and Nup133 share a conserved domain arrangement and tertiary structure (a second ancestral coatomer element, ACE2), indicating they descend from a common ancestor and form major alpha-helical building blocks of the NPC scaffold.\",\n      \"method\": \"Crystal structure determination and structural comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with structural conservation analysis\",\n      \"pmids\": [\"19674973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The N-terminal domain of Nup133, although largely dispensable for NPC assembly, is required for efficient anchoring of the dynein/dynactin complex to the nuclear envelope in prophase; this function is mediated through a molecular chain involving CENP-F and NudE/NudEL, and is critical for maintaining centrosome association with the NE at mitotic entry and contributing to bipolar spindle assembly.\",\n      \"method\": \"Dominant-negative N-terminal domain expression, co-immunoprecipitation, live-cell imaging, siRNA knockdown of pathway components, epistasis with RanBP2-BICD2 pathway\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, live imaging, genetic epistasis, domain mutants) in a single study\",\n      \"pmids\": [\"21383080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the C-terminal domain of yeast Nup133 (residues 944–1157) reveals an all-alpha-helical fold with 11 helices forming a compact structure, which differs from the human Nup133 C-terminal domain arrangement when bound to Nup107, reflecting structural divergence between homologs.\",\n      \"method\": \"X-ray crystallography at 1.9 Å resolution\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, but no functional mutagenesis in this study\",\n      \"pmids\": [\"21365675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Integrative modeling of full-length yeast Nup133 using SAXS, negative-stain EM, and chemical cross-linking identifies a conserved ALPS (ArfGAP1 lipid packing sensor) motif in the N-terminal domain; liposome interaction studies (in the 2020 follow-up) confirm this motif mediates membrane anchoring of the NPC, suggesting a conserved mechanism for NPC membrane association across eukaryotes.\",\n      \"method\": \"Integrative structural modeling (crystal structures, SAXS, EM), chemical cross-linking/mass spectrometry, mutational studies\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 structural modeling with mutagenesis; liposome binding confirmed in separate study\",\n      \"pmids\": [\"25139911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup133 is required for proper nuclear pore basket assembly in mouse embryonic stem cells; loss of Nup133 specifically perturbs formation of the nuclear basket (absence of Tpr in ~50% of NPCs and altered dynamics of Nup153), while the central domain of Nup133 mediates its role in assembling Tpr and Nup153 into the basket.\",\n      \"method\": \"Null mutant mESCs, single-pore detection, average NE fluorescence intensity, domain mapping with deletion mutants, FRAP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with domain-mapping rescue experiments and quantitative single-pore readouts\",\n      \"pmids\": [\"29791854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous NUP133 splicing mutation (c.3335-11T>A) inserts 9 bp of intronic sequence, impairs NUP133-NUP107 interaction by immunoprecipitation, and causes Galloway-Mowat syndrome; nup133-knockdown zebrafish phenocopy human disease features (microcephaly, underdeveloped glomeruli, podocyte foot process fusion) and are rescued by wild-type but not mutant human NUP133 mRNA.\",\n      \"method\": \"Immunoprecipitation of mutant vs. wild-type NUP133-NUP107 interaction, zebrafish morpholino knockdown with rescue by mRNA injection\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — IP-based interaction mapping combined with zebrafish rescue genetics\",\n      \"pmids\": [\"30427554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM/crystal structures of the full-length yeast Nup84-Nup133 CTD complex and the Nup133 NTD bound to nanobodies reveal high flexibility of the Nup84-Nup133 dimeric unit; the Nup133 NTD contains a structurally conserved ALPS motif confirmed by liposome interaction studies to mediate membrane binding.\",\n      \"method\": \"Cryo-EM and X-ray crystallography with nanobody-assisted crystallization, liposome interaction assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure determination combined with in vitro liposome binding assay\",\n      \"pmids\": [\"33247142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9-mediated loss of NUP133 in human podocytes disrupts nuclear pore assembly, alters the podocyte-specific transcriptome, and impairs cellular protrusion generation; SRNS-associated NUP133 mutations primarily impair Y-complex protein interaction and reduce NUP133 protein levels, causing a partial loss-of-function phenotype.\",\n      \"method\": \"CRISPR/Cas9 knockout and patient mutation knock-in in human podocytes, transcriptome analysis, nuclear pore assembly assay, cytoskeleton/protrusion imaging, protein interaction analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic editing with multiple readouts, but single-lab study\",\n      \"pmids\": [\"35455939\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP133 is a scaffold nucleoporin of the conserved Y-complex (Nup107-160/Nup84 complex) whose C-terminal alpha-helical domain anchors it to the NPC via tight interaction with Nup107, while its N-terminal seven-bladed beta-propeller contains a membrane-sensing ALPS motif that mediates NPC membrane anchoring; it is required for mRNA export, NPC distribution, nuclear basket assembly (recruiting Tpr and Nup153), and—through its N-terminal domain engaging a CENP-F/NudE/NudEL/dynein-dynactin chain at the nuclear envelope—for centrosome tethering and bipolar spindle assembly at mitotic entry.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Disruption or mutation of yeast NUP133 (RAT3) causes temperature-dependent nuclear accumulation of poly(A)+ RNA and constitutive clustering of nuclear pore complexes into one or a few regions of the nuclear envelope, establishing Nup133 as a nucleoporin required for mRNA export and proper NPC distribution.\",\n      \"method\": \"Yeast genetics (temperature-sensitive mutants, gene disruption), fluorescent in situ hybridization for poly(A)+ RNA, indirect immunofluorescence, electron microscopy, epitope tagging and co-localization with NPC markers\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, independently confirmed by two labs in the same year (PMID 7626806 and 7862658)\",\n      \"pmids\": [\"7626806\", \"7862658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Vertebrate Nup133 and Nup160 were identified as novel nucleoporins that bind Nup98 and Nup153 (via pulldowns from Xenopus egg extracts), form a complex with Nup107, Nup96, and Sec13 (the Nup160 complex), are accessible on the basket side of the pore, and specific Nup133/Nup160 fragments block poly(A)+ RNA export but not protein import or export.\",\n      \"method\": \"Pulldown from Xenopus egg extracts, protein purification and sequencing, co-immunoprecipitation, immunofluorescence, in vivo transport assays (transfection of dominant-negative fragments)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldowns, complex reconstitution in extracts, functional in vivo transport assay with dominant-negative fragments\",\n      \"pmids\": [\"11684705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The conserved Nup107-160 complex (containing Nup133) is critical for postmitotic NPC assembly: RNAi depletion of Nup133 or Nup107 in HeLa cells reduced nucleoporin levels and NPC density; immunodepletion of the entire complex from in vitro nuclear assembly reactions produced nuclei with a continuous NE but no NPCs, reversible only if the complex was added before closed NE formation.\",\n      \"method\": \"RNAi knockdown in HeLa cells, in vitro nuclear assembly assay with Xenopus egg extracts, immunodepletion, immunofluorescence, electron microscopy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro reconstitution/depletion combined with in vivo RNAi, multiple orthogonal readouts\",\n      \"pmids\": [\"12705868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human Nup133 contains two distinct domains: a C-terminal domain that mediates interaction with Nup107 (anchoring Nup133 to its subcomplex), and an N-terminal domain whose crystal structure reveals a seven-bladed beta-propeller with surface properties suggesting multiple protein interactions.\",\n      \"method\": \"Crystal structure determination of the N-terminal beta-propeller domain, deletion/domain mapping, co-immunoprecipitation to define Nup107-binding region\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with domain-function mapping\",\n      \"pmids\": [\"15557116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the human Nup107–Nup133 C-terminal domain complex reveals that both proteins form elongated structures interacting tightly via a compact interface in tail-to-tail fashion; structure-guided mutagenesis confirms that Nup107 is the critical anchor positioning Nup133 at the periphery of the NPC.\",\n      \"method\": \"Crystal structure determination, structure-guided mutagenesis, functional interaction assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation\",\n      \"pmids\": [\"18570875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structures of yNup170(979–1502) and hNup107(658–925)·hNup133(517–1156) reveal conserved domain arrangement and tertiary structure between Nup157/170 and Nup133, suggesting they descend from a common ancestral coatomer-like element (ACE); together with ACE1, these define the major alpha-helical building blocks of the NPC scaffold.\",\n      \"method\": \"Crystal structure determination, structural comparison, evolutionary analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with structural validation\",\n      \"pmids\": [\"19674973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The N-terminal domain of Nup133 (though largely dispensable for NPC assembly) is required for efficient anchoring of the dynein/dynactin complex to the nuclear envelope in prophase; Nup133 acts through an interaction network involving CENP-F and NudE/NudEL, and this molecular chain is critical for maintaining centrosome association with the NE at mitotic entry and contributes to bipolar spindle assembly.\",\n      \"method\": \"RNAi knockdown, dominant-negative domain expression, co-immunoprecipitation, live-cell imaging, immunofluorescence, genetic epistasis with RanBP2-BICD2 pathway\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, multiple dominant-negative constructs, live imaging, pathway epistasis\",\n      \"pmids\": [\"21383080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Integrative structural modeling of yeast Nup133 using crystal structures, SAXS, negative-stain EM, and cross-linking mass spectrometry identified an ArfGAP1 lipid packing sensor (ALPS) motif in Nup133; mutational studies confirm this motif, suggesting Nup133's ALPS mediates membrane anchoring of the NPC in the nuclear envelope.\",\n      \"method\": \"Crystal structure determination (VpNup133), SAXS (18 constructs), negative-stain EM, cross-linking mass spectrometry, mutagenesis, integrative structural modeling\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal structural methods plus mutagenesis in a single study\",\n      \"pmids\": [\"25139911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Nup133 in mouse embryonic stem cells specifically perturbs nuclear basket assembly: ~50% of NPCs lack Tpr, and Nup153 dynamics are altered; the central domain of Nup133 mediates its role in assembling Tpr and Nup153 into a properly configured nuclear basket, while Nup133 is dispensable for interphase and postmitotic NPC scaffold assembly in pluripotent mESCs.\",\n      \"method\": \"Null mutation in mice, single-pore detection by super-resolution microscopy, average NE-fluorescence intensity measurement, FRAP (Nup153 dynamics), domain mapping via rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null combined with single-pore resolution imaging, FRAP, and domain rescue\",\n      \"pmids\": [\"29791854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous NUP133 splicing mutation (c.3335-11T>A) causes Galloway-Mowat syndrome (microcephaly, brain anomalies, nephrotic syndrome); the mutation impairs NUP133–NUP107 interaction as shown by immunoprecipitation; nup133-knockdown zebrafish exhibit microcephaly, fewer neuronal cells, underdeveloped glomeruli, and podocyte foot process fusion, rescued by wild-type but not mutant human NUP133 mRNA.\",\n      \"method\": \"Whole exome sequencing, linkage analysis, immunoprecipitation (NUP133–NUP107 interaction), zebrafish morphant model, mRNA rescue experiments\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics combined with functional zebrafish rescue experiments and biochemical interaction assay\",\n      \"pmids\": [\"30427554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of full-length yeast Nup84–Nup133 C-terminal domain complex and the Nup133 N-terminal domain (nanobody-bound) reveal high flexibility of this dimeric unit; the Nup133 NTD contains a structurally conserved ALPS motif confirmed by liposome interaction studies to mediate membrane binding.\",\n      \"method\": \"Cryo-EM/X-ray crystallography with nanobody-bound complexes, liposome interaction assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro liposome binding assay confirming ALPS function\",\n      \"pmids\": [\"33247142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nup133 protein level declines in male but not female mouse oligodendrocyte progenitor cells (OPCs) following hyperoxia; Nrf1 is identified as a direct downstream transcriptional target of Nup133, and Nup133 regulates mitochondrial function and oxidative stress response through Nrf1.\",\n      \"method\": \"Cell culture (primary OPCs), hyperoxia treatment, western blotting, siRNA knockdown, reporter assays for Nrf1 transcriptional regulation\",\n      \"journal\": \"Molecular and cellular pediatrics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic follow-up, no direct binding assay between Nup133 and Nrf1\",\n      \"pmids\": [\"32844334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9-mediated NUP133 loss-of-function in human podocytes disrupts nuclear pore scaffold assembly, alters the podocyte-specific transcriptome, and impairs cellular protrusion generation; SRNS-related NUP133 point mutations show only mild defects but impair Y-complex protein interaction and reduce NUP133 protein levels, suggesting partial loss-of-function as the disease mechanism.\",\n      \"method\": \"CRISPR/Cas9 genome editing, RNA-seq transcriptome analysis, immunofluorescence (NPC assembly), co-immunoprecipitation (Y-complex interaction), cytoskeletal/protrusion assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with multiple readouts, but single lab\",\n      \"pmids\": [\"35455939\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP133 is a scaffold nucleoporin that anchors to the NPC periphery via its C-terminal interaction with NUP107, contributes to NPC biogenesis and proper NPC distribution (preventing clustering), promotes mRNA export, assembles the nuclear basket (recruiting Tpr and Nup153) through its central domain, uses an N-terminal ALPS motif for membrane anchoring of the NPC, and — through its N-terminal domain — recruits dynein/dynactin to the nuclear envelope via a CENP-F/NudE/NudEL chain to tether centrosomes at mitotic entry; loss-of-function mutations cause Galloway-Mowat syndrome and steroid-resistant nephrotic syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP133 is a scaffold nucleoporin of the Y-complex (Nup107-160 complex) that functions in mRNA export, nuclear pore complex distribution, nuclear basket assembly, membrane anchoring of the NPC, and centrosome tethering at mitotic entry. Its C-terminal alpha-helical domain forms a tight tail-to-tail interface with NUP107 that anchors NUP133 to the NPC periphery, while its N-terminal seven-bladed beta-propeller contains a conserved ALPS motif that mediates direct membrane binding via liposome interaction [PMID:15557116, PMID:18570875, PMID:33247142]. NUP133 is required for nuclear basket assembly—its central domain recruits Tpr and Nup153 to the pore—and its N-terminal domain engages a CENP-F/NudE/NudEL/dynein-dynactin chain at the nuclear envelope to maintain centrosome–NE association and bipolar spindle formation [PMID:29791854, PMID:21383080]. Homozygous NUP133 mutations that disrupt the NUP107 interaction cause Galloway-Mowat syndrome, characterized by microcephaly and nephrotic disease [PMID:30427554].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that NUP133 is an NPC component required for mRNA export and even NPC distribution resolved a key question about how individual nucleoporins contribute to pore function and positioning.\",\n      \"evidence\": \"Temperature-sensitive yeast mutants and gene disruptions analyzed by FISH, immunofluorescence, and electron microscopy\",\n      \"pmids\": [\"7626806\", \"7862658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of NPC clustering upon NUP133 loss unknown\", \"Whether mRNA export defect is direct or secondary to NPC malformation unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of vertebrate NUP133 within a stable Nup107-Nup96-Nup160 complex and demonstration that its fragments block poly(A)+ RNA export established conservation of its export role and placed it within a defined subcomplex.\",\n      \"evidence\": \"Pulldown from Xenopus egg extracts, protein sequencing, dominant-negative fragment transport assays\",\n      \"pmids\": [\"11684705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the subcomplex not yet resolved\", \"Mechanism by which NUP133 fragments block export unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Determination of the NUP133 N-terminal beta-propeller structure and mapping of the C-terminal NUP107-binding domain revealed a bipartite architecture with distinct functional surfaces.\",\n      \"evidence\": \"X-ray crystallography of human NUP133 N-terminal domain, domain mapping, interaction assays\",\n      \"pmids\": [\"15557116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the beta-propeller interaction surfaces unknown\", \"Full-length structure not available\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The crystal structure of the NUP107–NUP133 C-terminal complex defined the precise tail-to-tail interface and established NUP107 as the critical anchor for NUP133 at the NPC periphery.\",\n      \"evidence\": \"Crystal structure determination with structure-guided mutagenesis and binding assays\",\n      \"pmids\": [\"18570875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How this dimer is positioned within the full Y-complex not resolved\", \"Structural divergence from yeast homolog unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that the NUP133 N-terminal domain recruits dynein/dynactin to the nuclear envelope via a CENP-F/NudE/NudEL chain revealed an unexpected mitotic function in centrosome tethering and bipolar spindle assembly.\",\n      \"evidence\": \"Dominant-negative domain expression, co-immunoprecipitation, live-cell imaging, siRNA epistasis in human cells\",\n      \"pmids\": [\"21383080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner on the NUP133 beta-propeller not identified\", \"Whether this pathway operates in all cell types unknown\", \"Structural basis of CENP-F recognition not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Integrative structural modeling identified a conserved ALPS motif in the NUP133 N-terminal domain, providing the first molecular explanation for how the Y-complex contacts the nuclear envelope membrane.\",\n      \"evidence\": \"SAXS, negative-stain EM, chemical cross-linking/mass spectrometry, and mutational analysis of yeast Nup133\",\n      \"pmids\": [\"25139911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct membrane binding by the ALPS motif not yet demonstrated in vitro at this stage\", \"Contribution relative to other membrane-anchoring mechanisms at the NPC unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that NUP133 loss specifically abolishes nuclear basket assembly (Tpr and Nup153 recruitment) via its central domain distinguished NUP133's basket-organizing role from its other Y-complex functions.\",\n      \"evidence\": \"Nup133-null mouse embryonic stem cells with single-pore detection, domain deletion rescue, FRAP\",\n      \"pmids\": [\"29791854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct interaction between NUP133 central domain and basket nucleoporins not biochemically demonstrated\", \"Mechanism by which only ~50% of NPCs lose Tpr unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking a homozygous NUP133 splicing mutation to Galloway-Mowat syndrome, with zebrafish rescue proving causality, established NUP133 as a disease gene and connected impaired NUP107 interaction to nephrotic and neurological phenotypes.\",\n      \"evidence\": \"Patient genotyping, immunoprecipitation of mutant NUP133-NUP107, zebrafish morpholino knockdown with wild-type vs. mutant mRNA rescue\",\n      \"pmids\": [\"30427554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How partial NUP107 interaction loss leads specifically to podocyte and neuronal vulnerability unknown\", \"Whether other NUP133 mutations cause broader phenotypic spectrum untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM and crystallographic structures of the full-length yeast Nup84-Nup133 dimer confirmed high flexibility and validated ALPS-motif-mediated membrane binding by liposome assays, completing the structural picture of NUP133's membrane-sensing role.\",\n      \"evidence\": \"Cryo-EM, nanobody-assisted crystallography, liposome interaction assays\",\n      \"pmids\": [\"33247142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of ALPS motif to NPC membrane anchoring not tested by point mutation\", \"Whether membrane curvature sensing by ALPS plays a role in de novo NPC insertion unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR knockout and patient-mutation knock-in in human podocytes showed NUP133 loss disrupts NPC assembly, alters the podocyte transcriptome, and impairs cellular protrusions, providing a cellular mechanism for SRNS pathogenesis.\",\n      \"evidence\": \"CRISPR/Cas9 editing in human podocytes, transcriptome profiling, NPC assembly and cytoskeletal imaging\",\n      \"pmids\": [\"35455939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific transcriptional changes drive podocyte dysfunction not determined\", \"Whether protrusion defect is NPC-dependent or cytoskeleton-autonomous unclear\", \"Single-lab study awaiting independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of NUP133's interaction with CENP-F and its central domain's recruitment of nuclear basket components remain unresolved, as does the in vivo contribution of the ALPS motif to de novo NPC biogenesis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure of NUP133 with CENP-F or basket nucleoporins\", \"ALPS motif contribution to NPC insertion not tested by in vivo point mutation\", \"Cell-type-specific requirements for NUP133 functions largely unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2, 6, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"complexes\": [\n      \"Y-complex (Nup107-160 complex)\"\n    ],\n    \"partners\": [\n      \"NUP107\",\n      \"NUP96\",\n      \"NUP160\",\n      \"TPR\",\n      \"NUP153\",\n      \"CENPF\",\n      \"NDEL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP133 is a scaffold nucleoporin of the Nup107-160 (Y-complex) that is essential for nuclear pore complex biogenesis, proper NPC distribution across the nuclear envelope, mRNA export, and nuclear basket assembly. Its C-terminal domain anchors to Nup107 in a tail-to-tail arrangement positioning Nup133 at the NPC periphery [PMID:18570875], while its N-terminal β-propeller contains an ALPS motif that mediates direct membrane binding to tether the NPC to the nuclear envelope [PMID:25139911, PMID:33247142]. Beyond interphase NPC function, the N-terminal domain recruits dynein/dynactin to the nuclear envelope during prophase via a CENP-F/NudE/NudEL chain, thereby maintaining centrosome–NE association at mitotic entry [PMID:21383080], and the central domain is required for assembling Tpr and Nup153 into the nuclear basket [PMID:29791854]. Homozygous loss-of-function mutations in NUP133 cause Galloway-Mowat syndrome featuring microcephaly, brain anomalies, and nephrotic syndrome [PMID:30427554].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The first functional characterization established that Nup133 is required for two fundamental NPC-associated processes—mRNA export and the even distribution of pores across the nuclear envelope—answering whether this nucleoporin has roles beyond structural scaffolding.\",\n      \"evidence\": \"Yeast gene disruption and temperature-sensitive mutants with poly(A)+ RNA FISH, immunofluorescence, and EM\",\n      \"pmids\": [\"7626806\", \"7862658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of NPC clustering upon Nup133 loss not resolved\",\n        \"Direct versus indirect role in mRNA export undefined\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of vertebrate Nup133 as a subunit of a Nup107-containing complex (with Nup96 and Sec13) and demonstration that specific Nup133 fragments block poly(A)+ RNA export established the biochemical context of Nup133 within a larger NPC subcomplex.\",\n      \"evidence\": \"Pulldowns from Xenopus egg extracts, co-IP, dominant-negative fragment transport assays in vivo\",\n      \"pmids\": [\"11684705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and architectural position within the complex not determined\",\n        \"Binding interface between Nup133 and Nup107 not structurally resolved\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Depletion experiments demonstrated that the Nup107-160 complex (including Nup133) is essential for postmitotic NPC assembly, and must be incorporated before nuclear envelope closure, resolving the temporal requirement for this subcomplex in pore biogenesis.\",\n      \"evidence\": \"RNAi in HeLa cells combined with in vitro nuclear assembly in Xenopus egg extracts, immunodepletion and EM\",\n      \"pmids\": [\"12705868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contribution of Nup133 versus other Y-complex subunits to assembly not separated\",\n        \"Mechanism by which the complex seeds NPC insertion into membranes unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Structural and biochemical dissection of human Nup133 revealed a two-domain architecture—an N-terminal β-propeller and a C-terminal region that directly binds Nup107—providing the first molecular framework for understanding how Nup133 is anchored to its subcomplex while presenting an interaction surface for additional partners.\",\n      \"evidence\": \"X-ray crystallography of the N-terminal β-propeller, domain deletions and co-IP\",\n      \"pmids\": [\"15557116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Function of the N-terminal β-propeller surface unknown\",\n        \"Atomic details of the Nup107-binding interface not yet resolved\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The crystal structure of the Nup107–Nup133 C-terminal complex revealed a tail-to-tail elongated interface and confirmed via mutagenesis that Nup107 is the critical anchor positioning Nup133 at the NPC periphery, resolving the architecture of this dimer.\",\n      \"evidence\": \"X-ray crystallography and structure-guided mutagenesis\",\n      \"pmids\": [\"18570875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the Nup107–Nup133 dimer integrates into the full Y-complex ring not structurally resolved\",\n        \"Conformational dynamics in vivo unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural comparison of Nup133 with Nup157/170 demonstrated that NPC scaffold nucleoporins share an ancestral coatomer-like element (ACE), establishing the evolutionary origin of the NPC scaffold from protocoatomer building blocks.\",\n      \"evidence\": \"Crystal structures and structural homology analysis of yeast Nup170 and human Nup107·Nup133\",\n      \"pmids\": [\"19674973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of the ACE-fold conservation not tested directly\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that the Nup133 N-terminal domain recruits dynein/dynactin to the nuclear envelope during prophase via a CENP-F–NudE/NudEL chain revealed a mitotic function for this nucleoporin in centrosome tethering and bipolar spindle assembly, independent of its NPC scaffolding role.\",\n      \"evidence\": \"RNAi, dominant-negative domains, co-IP, live-cell imaging, epistasis with the RanBP2–BICD2 pathway in HeLa cells\",\n      \"pmids\": [\"21383080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the ALPS motif and dynein-recruitment function overlap spatially on the N-terminal domain not resolved\",\n        \"Regulation of the Nup133–CENP-F interaction across the cell cycle unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification and validation of an ArfGAP1 lipid packing sensor (ALPS) motif within the Nup133 N-terminal domain resolved how the NPC is anchored to the curved pore membrane, providing a direct membrane-sensing mechanism for scaffold nucleoporins.\",\n      \"evidence\": \"Integrative structural modeling (SAXS, EM, crosslinking MS, crystallography), mutagenesis of ALPS motif\",\n      \"pmids\": [\"25139911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative contribution of the ALPS motif to NPC stability in vivo not measured\",\n        \"Lipid specificity of the ALPS motif not characterized\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two parallel advances resolved: (1) Nup133's central domain specifically assembles the nuclear basket by recruiting Tpr and stabilizing Nup153, distinguishing basket assembly from scaffold assembly; and (2) a NUP133 splicing mutation causes Galloway-Mowat syndrome by disrupting NUP107 interaction, linking Nup133 loss-of-function to human neurodevelopmental and renal disease.\",\n      \"evidence\": \"Nup133-null mESCs with super-resolution microscopy and FRAP (basket assembly); human WES, co-IP, and zebrafish morphant rescue (disease)\",\n      \"pmids\": [\"29791854\", \"30427554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the central domain contacts Tpr and Nup153 at the molecular level is unknown\",\n        \"Genotype-phenotype spectrum across different NUP133 mutations remains incomplete\",\n        \"Whether basket deficiency or general NPC dysfunction drives Galloway-Mowat pathology not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR knockout of NUP133 in human podocytes confirmed that NPC scaffold assembly, the podocyte transcriptome, and cellular protrusion formation all depend on NUP133, while disease-associated point mutations cause partial loss-of-function through reduced Y-complex interaction and lower protein levels.\",\n      \"evidence\": \"CRISPR/Cas9 KO and point-mutation knock-in in human podocytes, RNA-seq, co-IP, protrusion assays\",\n      \"pmids\": [\"35455939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Results from a single lab; independent replication pending\",\n        \"Molecular basis for protrusion defects downstream of NPC disruption not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of Nup133's central-domain interaction with Tpr/Nup153 for basket assembly, the mechanistic relationship between NPC basket deficiency and Galloway-Mowat syndrome pathology, and how the three distinct functional surfaces (ALPS, dynein-recruitment, basket-assembly) are coordinately regulated across the cell cycle.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of Nup133–Tpr or Nup133–Nup153 interaction\",\n        \"Cell-cycle regulation of Nup133 N-terminal domain functions (ALPS vs dynein) unknown\",\n        \"Tissue-specific consequences of partial NUP133 loss not systematically studied\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 8, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"complexes\": [\n      \"Nup107-160 complex (Y-complex)\",\n      \"Nuclear pore complex (NPC)\"\n    ],\n    \"partners\": [\n      \"NUP107\",\n      \"NUP96\",\n      \"SEC13\",\n      \"NUP160\",\n      \"TPR\",\n      \"NUP153\",\n      \"CENPF\",\n      \"NUP98\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}