{"gene":"NUP188","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1996,"finding":"Yeast Nup188p was identified as a major constituent of the NPC, localizing to both cytoplasmic and nucleoplasmic faces of the NPC core. It physically interacts with the pore membrane protein Pom152p and the nucleoporin Nic96p. Null mutants appear normal, but certain dominant alleles cause NPC-associated nuclear envelope herniations and growth inhibition at 37°C. Depletion of Pom152p in nup188 null cells causes severe nuclear envelope deformations, establishing Nup188p as part of the octagonal core structure involved in NPC structural organization.","method":"Immunoelectron microscopy, immunofluorescence, co-fractionation with isolated NPCs, genetic interaction analysis (synthetic lethality), dominant allele phenotypic analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-fractionation, IEM localization, genetic epistasis, multiple orthogonal methods in one study","pmids":["8682855"],"is_preprint":false},{"year":1996,"finding":"The C-terminal domain of Nic96p functionally interacts with Nup188p in an allele-specific fashion; affinity purification of ProtA-Nup188p co-precipitated a fraction of Nic96p, establishing a physical interaction. Thermosensitive Nic96p mutations in its central domain inhibit NPC formation, and null mutants of NUP188 exhibit striking abnormalities in nuclear envelope and NPC morphology, placing Nup188p in the Nic96p-anchored structural network of the NPC.","method":"Allele-specific genetic interaction analysis, affinity purification (ProtA-Nup188p), electron microscopy of nuclear envelope morphology","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal physical interaction confirmed by affinity purification plus genetic epistasis with defined morphological readout","pmids":["8682854"],"is_preprint":false},{"year":1995,"finding":"Genetic interaction screens in yeast revealed that deletion of NUP188 alone is not lethal, but pairwise deletion combinations with POM152 or NUP170 are synthetically lethal, and NUP188 was identified as a major component comprising over one-fifth of the mass of the isolated yeast NPC together with Nup170p, Nup157p, Pom152p, and Nic96p.","method":"Synthetic lethal screen, direct microsequencing of NPC-enriched fractions, genetic complementation analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — biochemical isolation plus genetic epistasis, replicated across two complementary approaches","pmids":["8522578"],"is_preprint":false},{"year":2000,"finding":"Deletion of NUP188 (nup188-Δ) in yeast significantly increases passive nuclear envelope permeability: passive export rates of NLS-GFP reporters are faster, and equilibrium sieving limits for the NPC diffusion channel are larger than wild-type. This establishes Nup188p (together with Nup170p) as a determinant of the functional resting diameter of the NPC's central transport channel.","method":"In vivo fluorescence microscopy using NLS-GFP and NES-GFP reporters of varying sizes in nup188-Δ cells, passive diffusion measurements","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with quantitative in vivo transport assay and size-sieving readout","pmids":["10831607"],"is_preprint":false},{"year":1999,"finding":"Elevated levels of Ssa1p (but not Ssb1p) suppress the NLS-GFP nuclear localization defects of nup188-Δ cells, placing Nup188p functionally upstream of Hsp70-assisted NLS-directed import. The differential suppression mapped to the nuclear export signal (NES) of Ssb1p, not to ATPase or peptide-binding domain differences, demonstrating a specific functional connection between Nup188p and cytosolic Hsp70 in nuclear transport.","method":"Genetic suppression analysis in nup188-Δ yeast, GFP reporter localization, chimeric Hsp70 constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined transport readout, single lab","pmids":["10347213"],"is_preprint":false},{"year":1997,"finding":"N-Nup145p (the GLFG-containing N-terminal cleavage product of Nup145p) becomes essential in a nup188 mutant background, demonstrating a synthetic lethal genetic interaction. Generation of the free N-domain by in vivo cleavage is required to complement this interaction, placing Nup188p in a functional network with GLFG-nucleoporins at the NPC.","method":"Synthetic lethality analysis in nup188 mutant background, domain complementation assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined domain requirement, single study","pmids":["9305650"],"is_preprint":false},{"year":2000,"finding":"Vertebrate Nup188 was identified using an organelle trap assay in Xenopus egg extracts. Xenopus Nup188 exists in a stable complex with xNup93 and xNup205, does not bind WGA directly but associates indirectly via N-acetylglucosamine-modified nucleoporins, and can assemble into annulate lamellae (a cytoplasmic NPC mimic). Human NUP188 was also identified as an ortholog.","method":"Organelle trap assay (affinity selection on WGA-Sepharose + in vitro annulate lamellae assembly), co-immunoprecipitation, biotinylation tagging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical reconstitution in Xenopus extract with in vitro pore assembly plus co-purification, multiple orthogonal methods","pmids":["11029043"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of yeast Nup188 was determined, revealing an extended stack of helices where the N-terminal ~130 kDa segment forms an intricate closed ring and the C-terminal region is a superhelical structure with distant similarity to S-shaped nuclear transport receptors (NTRs). Both Nup188 and Nup192 specifically bind FG-repeats and can translocate through NPCs by facilitated diffusion, blurring the distinction between stationary scaffold nucleoporins and soluble NTRs.","method":"X-ray crystallography (structure determination), FG-repeat binding assays, in vivo NPC translocation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro FG-repeat binding and in vivo translocation assays, multiple orthogonal methods","pmids":["23795296"],"is_preprint":false},{"year":2013,"finding":"Human Nup188 localizes to spindle poles during mitosis through its C-terminal region. Depletion of Nup188 causes failure of chromosome alignment at the metaphase plate, mitotic arrest via the spindle assembly checkpoint, and loss of robust K-fiber formation. Nup188 physically interacts with NuMA, and NuMA localization to spindle poles is perturbed in Nup188-depleted cells, establishing a mitotic function for Nup188 in chromosome segregation via K-fiber formation and NuMA recruitment.","method":"RNAi knockdown with live-cell imaging, immunofluorescence for spindle pole localization, co-immunoprecipitation (Nup188-NuMA interaction), spindle assembly checkpoint analysis","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 2 — KD with defined cellular phenotype plus co-IP and domain-mapping, multiple orthogonal methods","pmids":["23551833"],"is_preprint":false},{"year":2016,"finding":"Nup188 (together with Nup205) assists Nup93 in mediating repression of the HOXA gene cluster at the nuclear periphery. Depletion of the Nup93 sub-complex (Nup93/Nup188/Nup205) significantly upregulates HOXA gene expression, disengages the HOXA locus from the nuclear periphery (by 3D-FISH), increases active histone marks (H3K9ac), decreases repressive marks (H3K27me3), and increases transcription elongation marks (H3K36me3) on HOXA1.","method":"siRNA knockdown, ChIP, 3D-FISH, histone mark analysis by ChIP, RT-qPCR for gene expression","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, 3D-FISH, histone marks), single lab","pmids":["27980680"],"is_preprint":false},{"year":2017,"finding":"GLFG repeats of Nup116 function redundantly with Nup188, a nonessential scaffold nucleoporin, to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly. Direct in vitro binding between GLFG-containing FG repeats and multiple scaffold Nups including Nup188 was demonstrated, revealing a structural 'Velcro' role for natively unfolded FG repeats in linking NPC subcomplexes.","method":"In vitro binding assays (FG-repeat/scaffold interaction), genetic epistasis (nup116Δ nup188 double mutants), in vivo NPC assembly assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro reconstitution of FG-repeat binding plus genetic epistasis, replicated with multiple scaffold Nups","pmids":["29033133"],"is_preprint":false},{"year":2018,"finding":"In budding yeast, Brl1 interacts with Nup188 by co-immunoprecipitation and with NPC components by split-YFP analysis. Brr6/Brl1 associate transiently with NPC assembly sites and promote NPC biogenesis; depletion causes NPC biogenesis defects while assembled NPCs remain intact, placing Nup188 within the Brl1-dependent NPC assembly pathway.","method":"Co-immunoprecipitation, split-YFP interaction analysis, conditional degron depletion, fluorescence microscopy of NPC assembly","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus split-YFP plus functional degron depletion, single lab","pmids":["29439116"],"is_preprint":false},{"year":2018,"finding":"Quantitative fluorescence microscopy (NuRIM) revealed that Nup188 and its paralog Nup192 form a paralog pair whose altered expression leads to significant changes in NPC stoichiometry: overexpression of one leads to substitution for the other, revealing compositional plasticity at the NPC inner ring.","method":"Quantitative fluorescence microscopy (NuRIM), genetic manipulation of Nup188/Nup192 expression levels","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative imaging with functional manipulation, single lab","pmids":["29632211"],"is_preprint":false},{"year":2019,"finding":"TDP-43 controls mRNA splicing of NUP188; complete knockout of TDP-43 in human cells results in aberrant Nup188 mRNA splicing, and this is accompanied by nuclear envelope morphological defects, establishing TDP-43 as a trans-acting splicing regulator of NUP188.","method":"TDP-43 knockout cell lines, transcriptomic analysis, RT-PCR validation of splicing defects, cell biological analysis of nuclear envelope morphology","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 — KO with transcriptomic and direct splicing validation, single lab","pmids":["31527135"],"is_preprint":false},{"year":2020,"finding":"Nup188 populates centrosomes (pericentriolar material, PCM) with newly synthesized protein that does not exchange with NPCs even after mitotic NPC breakdown. The PCM pool is subject to proteasomal degradation while the NPC pool is not, establishing differential turnover as a mechanism segregating Nup188 between the two compartments. Nup188 directly binds Cep152 and functions in centriole duplication at or upstream of Sas6 loading, linking its centrosomal role to congenital heart disease mechanisms.","method":"Pulse-chase fluorescent labeling, proximity-labeling (BioID), super-resolution microscopy, proteasome inhibitor experiments, direct binding assay (Nup188-Cep152), Nup188 depletion with Sas6 loading assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods (pulse-chase, BioID, super-resolution, direct binding, functional depletion), single lab but comprehensive","pmids":["32211895"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM and crystal structures of intact Nup188 (and Nup192) scaffold hubs bound to linker nucleoporin binding regions (Nic96, Nup145N, Nup53) were determined, revealing Nup188 as a question mark-shaped keystone of two evolutionarily conserved hetero-octameric inner ring complexes. Linkers bind to scaffold surface pockets through short defined motifs. Quantitative docking into cryo-ET maps of constricted and dilated NPCs positioned Nup188 in the intact fungal and human NPC and revealed that the linker-scaffold network allows inner ring constriction/dilation while outer ring spokes are cross-link stapled and restricted from dilation.","method":"Single-particle cryo-EM, X-ray crystallography, biochemical reconstitution, cryo-ET docking, structure-guided mutagenesis in S. cerevisiae","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — multiple high-resolution structures combined with biochemical reconstitution and in vivo functional validation, comprehensive study","pmids":["35679425"],"is_preprint":false},{"year":2022,"finding":"NUP188 was identified as a Nesprin-2-interacting partner of the LINC complex at the nuclear envelope. Cytosol-localized SV40 polyomavirus is targeted to the nuclear envelope via Nesprin-2, which positions NUP188/NPC to capture the virus and facilitate nuclear translocation. This defines NUP188 as a physical bridge between the LINC complex and NPC for cargo handoff.","method":"Co-immunoprecipitation (Nesprin-2/NUP188 interaction), siRNA knockdown with viral infection assays, fluorescence microscopy tracking of SV40 nuclear entry","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP interaction plus functional knockdown with defined viral entry readout, single lab","pmids":["36067270"],"is_preprint":false},{"year":2011,"finding":"Morpholino knockdown of NUP188 in Xenopus strongly disrupts both morphological left-right (LR) development and expression of pitx2, a molecular marker of LR patterning, identifying NUP188 as a gene required for LR body patterning, likely through a cilia-related mechanism at the gastrocoel roof plate LR organizer.","method":"Morpholino knockdown in Xenopus, in situ hybridization for pitx2 expression, morphological scoring of LR defects","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — morpholino KD with molecular and morphological readouts in model organism, part of a broader validated screen","pmids":["21282601"],"is_preprint":false},{"year":2018,"finding":"A cold-sensitive nup188-brr7 allele causes defects in select protein import pathways as well as mRNA export in S. cerevisiae, linking Nup188 function specifically to nucleocytoplasmic transport through the Nic96 nucleoporin complex.","method":"Genetic screen (cold-sensitive mRNA export), dT50 in situ hybridization for poly-A RNA export, protein import assays in nup188 mutant","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — allele-specific genetic and transport functional analysis, single lab","pmids":["30021831"],"is_preprint":false},{"year":2025,"finding":"A genome-wide screen in yeast identified Nup188 as required for break-induced replication (BIR) completion, acting later than Nup84. Nup188 functions after DNA synthesis to support BIR repair completion, placing it sequentially in the BIR pathway distinct from its NPC structural role.","method":"Genome-wide genetic screen for BIR deficiency, validation by epistasis analysis of nup188 deletion in BIR assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide screen with targeted validation and epistasis placement, single study","pmids":["41398407"],"is_preprint":false},{"year":1999,"finding":"Full-length Pom152p (including its lumenal C-terminal domain) is required to rescue nup188 mutations, while the N-terminal domain alone can rescue nic96 and nup59 mutants, demonstrating that Nup188p's functional interaction with Pom152p requires the lumenal structures of Pom152p and implicating the pore membrane-to-scaffold connection in NUP188 function.","method":"Domain complementation assays of Pom152p in nup188 and other nup mutant backgrounds, topology mapping by alkaline extraction and protease protection","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — systematic domain complementation in defined genetic backgrounds, single lab","pmids":["9988776"],"is_preprint":false}],"current_model":"NUP188 encodes a large scaffold nucleoporin that forms a question mark-shaped keystone of the NPC inner ring, interacting physically with Nic96/Nup93, Pom152, Nup205, and linker nucleoporins to establish the NPC's structural integrity and central transport channel diameter; beyond its NPC role, Nup188 localizes to the pericentriolar material where it directly binds Cep152 to promote centriole duplication, localizes to spindle poles to recruit NuMA and facilitate K-fiber formation during mitosis, assists Nup93 in tethering and repressing the HOXA gene cluster at the nuclear periphery, functions in left-right body patterning via cilia-related mechanisms, and binds FG-repeats through an NTR-like fold allowing it to translocate through NPCs by facilitated diffusion."},"narrative":{"teleology":[{"year":1995,"claim":"The initial question—what are the principal mass components of the NPC scaffold?—was addressed by direct microsequencing of isolated yeast NPCs, which identified Nup188 as constituting a major fraction of total NPC mass and revealed synthetic lethal interactions with POM152 and NUP170, establishing Nup188 within a redundant structural scaffold network.","evidence":"Microsequencing of purified yeast NPC fractions combined with synthetic lethal screens in S. cerevisiae","pmids":["8522578"],"confidence":"High","gaps":["Precise stoichiometry and position of Nup188 within the NPC were not resolved","Vertebrate ortholog was not yet identified"]},{"year":1996,"claim":"The question of where Nup188 sits within the NPC and which partners anchor it was resolved by immuno-EM localizing Nup188 to both faces of the NPC core and by demonstrating direct physical interactions with Nic96p and Pom152p, defining the inner-ring Nic96–Nup188 axis as a central organizational module.","evidence":"Immuno-electron microscopy, affinity purification (ProtA-Nup188p), allele-specific genetic interaction analysis in S. cerevisiae","pmids":["8682855","8682854"],"confidence":"High","gaps":["Structural basis of Nic96–Nup188 interaction was unknown","Contribution of Nup188 to transport selectivity was not measured"]},{"year":1999,"claim":"The functional requirement for the Pom152 lumenal domain in rescuing nup188 mutations, and the genetic connection between Nup188 deletion and Hsp70-assisted import, together established that Nup188 functionally bridges the pore membrane and the transport machinery.","evidence":"Domain complementation assays of Pom152 in nup188 mutant backgrounds; genetic suppression of nup188Δ import defects by Ssa1p overexpression in S. cerevisiae","pmids":["9988776","10347213"],"confidence":"Medium","gaps":["Direct binding interface between Nup188 and the Pom152 lumenal domain was not mapped","Mechanism by which Hsp70 suppresses nup188Δ transport defects was not resolved"]},{"year":2000,"claim":"The question of whether Nup188 has a functional role in transport selectivity—beyond passive scaffolding—was answered: nup188Δ cells show an enlarged NPC diffusion channel, demonstrating that Nup188 is a determinant of the NPC's size-exclusion barrier.","evidence":"Quantitative in vivo fluorescence transport assays with NLS/NES-GFP reporters of varying sizes in nup188Δ S. cerevisiae; identification of vertebrate Nup188 in Xenopus extract NPC assemblies","pmids":["10831607","11029043"],"confidence":"High","gaps":["How Nup188 physically restricts channel diameter was structurally undefined","Vertebrate Nup188 function in transport had not been tested"]},{"year":2011,"claim":"Whether NUP188 functions outside nucleocytoplasmic transport was an open question; morpholino knockdown in Xenopus revealed a requirement for NUP188 in left–right body patterning, likely via cilia at the gastrocoel roof plate, extending NUP188 biology to developmental signaling.","evidence":"Morpholino knockdown in Xenopus embryos with pitx2 in situ hybridization and LR morphological scoring","pmids":["21282601"],"confidence":"Medium","gaps":["Direct ciliary localization of Nup188 in the LR organizer was not shown","Whether the phenotype is NPC-dependent or NPC-independent was not resolved"]},{"year":2013,"claim":"Two landmark studies resolved the structure and an unexpected NPC-external function: the crystal structure revealed an NTR-like fold that binds FG-repeats and enables NPC translocation, while RNAi in human cells showed spindle-pole localization during mitosis with NuMA recruitment enabling K-fiber formation—establishing Nup188 as both a scaffold and a mobile, multifunctional protein.","evidence":"X-ray crystallography of yeast Nup188 with FG-repeat binding and in vivo translocation assays; RNAi knockdown with live-cell imaging, co-IP (Nup188–NuMA), and K-fiber analysis in human cells","pmids":["23795296","23551833"],"confidence":"High","gaps":["Atomic-resolution structure of full-length vertebrate NUP188 was lacking","Whether mitotic and interphase pools are independently regulated was unknown"]},{"year":2016,"claim":"The discovery that depletion of Nup188 (as part of the Nup93 sub-complex) derepresses the HOXA gene cluster and displaces it from the nuclear periphery established a chromatin-regulatory role, answering whether inner-ring nucleoporins participate in gene silencing.","evidence":"siRNA knockdown with ChIP for histone marks, 3D-FISH for locus positioning, RT-qPCR in human cells","pmids":["27980680"],"confidence":"Medium","gaps":["Whether Nup188 contributes independently of Nup93 to HOXA repression was not isolated","Genome-wide scope of Nup188 chromatin regulation was not assessed"]},{"year":2018,"claim":"Multiple studies consolidated the NPC assembly and transport roles: FG-repeat 'Velcro' linkages with Nup188 stabilize late NPC assembly, Brl1 transiently recruits Nup188 during NPC biogenesis, compositional plasticity between Nup188 and Nup192 was quantified, and a cold-sensitive allele linked Nup188 to both protein import and mRNA export pathways.","evidence":"In vitro FG-repeat binding plus genetic epistasis (Cell); co-IP and split-YFP with Brl1 (JCB); quantitative fluorescence NuRIM (PNAS); cold-sensitive allele transport assays (G3), all in S. cerevisiae","pmids":["29033133","29439116","29632211","30021831"],"confidence":"High","gaps":["Temporal order of scaffold assembly involving Nup188 was not fully resolved","Whether Nup188/Nup192 plasticity exists in metazoans was not tested"]},{"year":2020,"claim":"The centrosomal function of Nup188 was mechanistically dissected: newly synthesized Nup188 populates the pericentriolar material independently of NPC pools, directly binds Cep152, and is required for Sas6 loading during centriole duplication, with differential proteasomal degradation segregating centrosomal and NPC pools.","evidence":"Pulse-chase fluorescent labeling, BioID proximity labeling, super-resolution microscopy, direct binding assays (Nup188–Cep152), Sas6 loading assays upon Nup188 depletion in human cells","pmids":["32211895"],"confidence":"High","gaps":["Structural basis of Nup188–Cep152 binding was not determined","Whether the centrosomal pool contributes to congenital heart disease mechanisms in vivo remains to be established in animal models"]},{"year":2022,"claim":"High-resolution cryo-EM structures of Nup188 bound to linker nucleoporins defined it as the question-mark-shaped keystone of two hetero-octameric inner-ring complexes, and docking into cryo-ET maps of constricted/dilated NPCs explained how the linker–scaffold network permits inner-ring dilation; separately, Nup188 was shown to bridge the LINC complex (Nesprin-2) to the NPC for SV40 virus nuclear entry.","evidence":"Single-particle cryo-EM and X-ray crystallography with cryo-ET docking and structure-guided mutagenesis in S. cerevisiae (Science); co-IP and siRNA knockdown with viral infection assays in human cells (PLoS Pathog)","pmids":["35679425","36067270"],"confidence":"High","gaps":["Full in situ structure of the human NPC inner ring at atomic resolution was not achieved","Generality of the LINC–NPC handoff to non-viral cargoes was untested"]},{"year":2025,"claim":"A genome-wide screen identified Nup188 as required for break-induced replication (BIR) completion at a step after DNA synthesis, expanding its roles to DNA repair and placing it sequentially downstream of the Nup84 outer-ring complex in BIR.","evidence":"Genome-wide genetic screen for BIR deficiency with epistasis validation in S. cerevisiae","pmids":["41398407"],"confidence":"Medium","gaps":["Molecular mechanism by which Nup188 supports BIR completion is unknown","Whether this reflects a transport-dependent or NPC-tethering-dependent role was not distinguished"]},{"year":null,"claim":"Key unresolved questions include: (1) the atomic-resolution in situ architecture of metazoan NPC inner rings containing NUP188, (2) the structural basis of Nup188's centrosomal interactions and whether centriole duplication defects underlie congenital heart disease in vivo, (3) whether chromatin-regulatory and BIR functions are NPC-scaffold-dependent or reflect moonlighting of soluble Nup188 pools, and (4) the mechanism linking NUP188 to left–right patterning.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in situ atomic-resolution metazoan NPC structure with NUP188 resolved","Centrosomal function not validated in animal disease models","Chromatin and BIR mechanisms not dissected from NPC transport functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,6,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,6,15,16]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[8,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,14]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[10,11,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[19]}],"complexes":["NPC inner ring complex (Nup93 sub-complex)","Nup93–Nup188–Nup205 complex"],"partners":["NUP93","NUP205","POM152","NIC96","NUMA1","CEP152","SYNE2","BRL1"],"other_free_text":[]},"mechanistic_narrative":"NUP188 encodes a large scaffold nucleoporin that serves as a question-mark-shaped keystone of the nuclear pore complex (NPC) inner ring, where it establishes structural integrity, sets the resting diameter of the central transport channel, and enables NPC constriction–dilation dynamics through a linker–scaffold network with Nic96/Nup93, Nup205, Pom152, and linker nucleoporins [PMID:8682855, PMID:10831607, PMID:35679425]. Its NTR-like fold binds FG-repeat domains and allows facilitated diffusion through the NPC, blurring the classical distinction between stationary scaffold and mobile transport factors [PMID:23795296, PMID:29033133]. Beyond the NPC, NUP188 localizes to centrosomes where it directly binds Cep152 to promote centriole duplication, to mitotic spindle poles where it recruits NuMA for K-fiber formation, and to the nuclear periphery where it participates with Nup93 in HOXA gene cluster repression [PMID:32211895, PMID:23551833, PMID:27980680]. NUP188 is also required for left–right body axis patterning in Xenopus, likely via cilia-dependent signaling [PMID:21282601]."},"prefetch_data":{"uniprot":{"accession":"Q5SRE5","full_name":"Nucleoporin NUP188","aliases":[],"length_aa":1749,"mass_kda":196.0,"function":"Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope (Probable). Required for proper protein transport into the nucleus (PubMed:32275884)","subcellular_location":"Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q5SRE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP188","classification":"Not Classified","n_dependent_lines":160,"n_total_lines":1208,"dependency_fraction":0.13245033112582782},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUP214","stoichiometry":4.0},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP188","total_profiled":1310},"omim":[{"mim_id":"618804","title":"SANDESTIG-STEFANOVA SYNDROME; SANDSTEF","url":"https://www.omim.org/entry/618804"},{"mim_id":"615587","title":"NUCLEOPORIN, 188-KD; NUP188","url":"https://www.omim.org/entry/615587"},{"mim_id":"615130","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 11; GALNT11","url":"https://www.omim.org/entry/615130"},{"mim_id":"614352","title":"NUCLEOPORIN, 205-KD; NUP205","url":"https://www.omim.org/entry/614352"},{"mim_id":"614351","title":"NUCLEOPORIN, 93-KD; NUP93","url":"https://www.omim.org/entry/614351"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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protein Pom152p and nucleoporin Nic96p, and is required for structural organization of the NPC and nuclear envelope — null mutants appear normal but certain alleles cause dominant NPC-associated nuclear envelope herniations; depletion of Pom152p in nup188 null cells causes severe nuclear envelope deformations.\",\n      \"method\": \"Immunoelectron microscopy, cofractionation, genetic analysis (null and dominant alleles), double-mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal physical interaction, immunoEM localization, functional genetic epistasis, replicated across two companion papers\",\n      \"pmids\": [\"8682855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminal domain of Nic96p functionally interacts with Nup188p in an allele-specific fashion, and affinity purification of ProtA-Nup188p co-purifies a fraction of Nic96p, demonstrating a physical interaction; Nic96p thermosensitive mutations in its central domain inhibit nuclear pore formation.\",\n      \"method\": \"Affinity purification (ProtA-Nup188p), allele-specific genetic interaction, temperature-sensitive mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown with genetic validation, two independent labs\",\n      \"pmids\": [\"8682854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Genetic interactions between Nup188p, Pom152p, Nup170p, and Nic96p were established: pairwise deletions of POM152, NUP170, or NUP188 are synthetically lethal, placing these proteins in a functionally interdependent group comprising >1/5 of the yeast NPC mass.\",\n      \"method\": \"Synthetic lethal screen, gene deletion, genetic epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic genetic epistasis with multiple pairwise combinations, replicated\",\n      \"pmids\": [\"8522578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Deletion of NUP188 (nup188-Δ) in yeast increases passive nuclear envelope permeability: passive export rates of NLS-GFP reporters are significantly faster and equilibrium sieving limits for the NPC diffusion channel are greater than wild-type, demonstrating that Nup188p contributes to establishing the functional resting diameter of the NPC central transport channel.\",\n      \"method\": \"In vivo GFP reporter passive transport assay, nup188 null mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined transport phenotype using multiple NLS-GFP reporters\",\n      \"pmids\": [\"10831607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Elevated levels of Ssa1p (Hsp70) suppress the NLS-GFP nuclear localization defects of nup188-Δ cells, while Ssb1p (which contains a nuclear export signal) does not, establishing that the role of cytosolic Hsp70 in NLS-directed import is pathway-specific and that Nup188p loss creates an import defect that can be compensated by increased cytosolic Hsp70 availability.\",\n      \"method\": \"Genetic suppression assay, GFP reporter nuclear localization in nup188-Δ yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic suppression with mechanistic follow-up, single lab\",\n      \"pmids\": [\"10347213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Full-length Pom152p (including its lumenal C-terminal domain) is required to rescue nup188 mutations, while partial Pom152p constructs rescue other NPC mutations, indicating that lumenal NE structures play a specific functional role in supporting Nup188p-dependent NPC architecture.\",\n      \"method\": \"Complementation assay with Pom152p domain truncations in nup188 mutant background\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function complementation, single lab\",\n      \"pmids\": [\"9988776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The N-terminal GLFG-containing domain of Nup145p (N-Nup145p) becomes essential in a nup188 mutant background, and generation of a free N-domain by in vivo cleavage is required for complementation of the nup188 synthetic lethal interaction, placing N-Nup145p and Nup188p in the same functional pathway.\",\n      \"method\": \"Genetic epistasis, in vivo cleavage assay, synthetic lethality complementation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with mechanistic dissection of domain requirements\",\n      \"pmids\": [\"9305650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Vertebrate (Xenopus/human) Nup188 was identified and shown to exist in a complex with Nup93 (xNup93) and Nup205 (xNup205) in Xenopus egg extracts; this complex does not bind WGA directly but associates indirectly via N-acetylglucosamine-modified nucleoporins.\",\n      \"method\": \"Organelle trap assay (WGA-Sepharose affinity selection + annulate lamellae assembly), co-complex identification, molecular cloning\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel two-step biochemical assay identifying complex with two partner nucleoporins\",\n      \"pmids\": [\"11029043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Morpholino knockdown of NUP188 in Xenopus strongly disrupts morphological left-right (LR) development and expression of pitx2 (a molecular marker of LR patterning), identifying NUP188 as a gene required for LR body patterning.\",\n      \"method\": \"Morpholino knockdown in Xenopus, in situ hybridization for pitx2, morphological scoring of LR defects\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined molecular and morphological phenotype readouts\",\n      \"pmids\": [\"21282601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human NUP188 localizes to spindle poles during mitosis via its C-terminal region; Nup188-depleted cells show failure of chromosome alignment at the metaphase plate, robust K-fiber defects, and perturbed NuMA localization to spindle poles. Nup188 directly interacts with NuMA, suggesting it promotes chromosome alignment through K-fiber formation and NuMA recruitment.\",\n      \"method\": \"siRNA knockdown, live/fixed imaging, co-immunoprecipitation (Nup188-NuMA interaction), mitotic phenotype analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying binding partner, KD with defined mitotic phenotype, localization experiment with functional consequence\",\n      \"pmids\": [\"23551833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The structure of Nup188 was determined: it folds into an extended stack of helices where an N-terminal ~130 kDa segment forms an intricate closed ring and the C-terminal region is a superhelical structure with distant similarity to flexible S-shaped nuclear transport receptors (NTRs). Nup188 and its paralog Nup192 specifically bind FG-repeats and can translocate through NPCs by facilitated diffusion, like NTRs.\",\n      \"method\": \"Crystal structure determination, FG-repeat binding assay (in vitro), facilitated diffusion/NPC translocation assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with in vitro binding assay and functional translocation assay\",\n      \"pmids\": [\"23795296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nup188 and Nup205 assist Nup93 in repressing HOXA gene expression: ChIP shows Nup93 enrichment at HOXA promoters; depletion of the Nup93 sub-complex (including Nup188) disengages the HOXA locus from the nuclear periphery, increases active histone marks (H3K9ac), decreases repressive marks (H3K27me3) on HOXA1 promoter, and upregulates HOXA gene expression.\",\n      \"method\": \"ChIP, siRNA knockdown, 3D-FISH, histone mark analysis, gene expression measurement\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, 3D-FISH, histone marks), single lab\",\n      \"pmids\": [\"27980680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GLFG repeats of Nup116 function redundantly with Nup188 (a nonessential scaffold Nup) to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly; direct binding of GLFG-containing FG repeats to multiple scaffold Nups including Nup188 was demonstrated in vitro.\",\n      \"method\": \"In vitro FG-repeat binding assay, yeast genetic analysis (nup116Δ nup188 double mutants), NPC assembly assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding combined with genetic epistasis, published in high-impact journal\",\n      \"pmids\": [\"29033133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Quantitative fluorescence microscopy in budding yeast showed that Nup188 and its paralog Nup192 can substitute for each other: altered expression of one paralog leads to significant changes in NPC stoichiometry, inducing either voids or substitution of one paralog by the other, demonstrating compositional plasticity.\",\n      \"method\": \"Quantitative fluorescence microscopy (NuRIM pipeline), NPC stoichiometry measurement, expression manipulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative in vivo measurement with functional consequence, single lab\",\n      \"pmids\": [\"29632211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Brl1 (a conserved NE integral membrane protein) interacts with Nup188 by immunoprecipitation and by split-YFP analysis, and is required for NPC biogenesis, placing Nup188 in the context of NPC assembly at the nuclear envelope membrane.\",\n      \"method\": \"Co-immunoprecipitation, split-YFP bimolecular fluorescence complementation, degron depletion\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and split-YFP identifying interaction, single lab\",\n      \"pmids\": [\"29439116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TDP-43 controls mRNA splicing of Nup188; loss of TDP-43 in human knockout cells causes mis-splicing of the NUP188 transcript, linking TDP-43 function to NPC integrity through post-transcriptional regulation of Nup188.\",\n      \"method\": \"Human TDP-43 KO cells, transcriptomic/splicing analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with transcriptomic validation, single lab\",\n      \"pmids\": [\"31527135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nup188 populates centrosomes with newly synthesized protein that does not exchange with NPCs even after mitotic NPC breakdown; the centrosomal (PCM) pool is subject to proteasomal degradation while the NPC pool is not. Nup188 directly binds Cep152 (a PCM component) and functions in centriole duplication at or upstream of Sas6 loading, establishing a non-NPC role for Nup188 in centriole duplication.\",\n      \"method\": \"Pulse-chase fluorescent labeling, proximity labeling (BioID), super-resolution microscopy, direct binding assay (Nup188-Cep152), proteasome inhibitor treatment, loss-of-function centriole duplication assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (pulse-chase, proximity labeling, direct binding, functional KD), single study with rigorous controls\",\n      \"pmids\": [\"32211895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal and cryo-EM structures of Nup188 and Nup192 bound to linker nucleoporins (Nic96, Nup145N, Nup53) were determined, revealing that Nup188 forms a question mark-shaped keystone of an evolutionarily conserved hetero-octameric inner ring complex. Linkers bind to Nup188 surface pockets through short defined motifs. Structure-guided mutagenesis in S. cerevisiae confirmed the physiological relevance, and docking into cryo-ET maps positioned Nup188 in both constricted and dilated NPC states, showing that the linker-scaffold gives rise to eight relatively rigid inner ring spokes with flexible interconnections allowing lateral channel formation.\",\n      \"method\": \"Crystal structure, single-particle cryo-EM, cryo-ET docking, biochemical reconstitution, structure-guided mutagenesis in yeast\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution + crystal/cryo-EM structures + mutagenesis + cryo-ET composite structure in single comprehensive study\",\n      \"pmids\": [\"35679425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUP188 was identified as a Nesprin-2-interacting partner at the nuclear pore complex: SV40 polyomavirus uses Nesprin-2 of the LINC complex to target the nuclear envelope and then engages NUP188 at the NPC for nuclear translocation, revealing a physical proximity between Nesprin-2 and NUP188.\",\n      \"method\": \"Co-immunoprecipitation (Nesprin-2/NUP188), viral infection assay, loss-of-function\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP identifying interaction, functional viral entry assay, single lab\",\n      \"pmids\": [\"36067270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A cold-sensitive nup188-brr7 allele in S. cerevisiae causes defects in both select protein import pathways and mRNA export, demonstrating that Nup188 (as a component of the Nic96 nucleoporin complex) contributes to nucleocytoplasmic transport.\",\n      \"method\": \"Cold-sensitive mutant screen, dT50 in situ hybridization (poly-A RNA accumulation), protein import assay\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific transport assay with two readouts, single lab\",\n      \"pmids\": [\"30021831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a genome-wide screen in yeast, Nup188 was identified as functioning late in break-induced replication (BIR) to support DNA repair completion, acting after Nup84 (which functions before DNA synthesis), placing Nup188 in a sequential NPC-dependent step in BIR.\",\n      \"method\": \"Genome-wide genetic screen, BIR assay, epistasis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen with epistasis validation, single lab\",\n      \"pmids\": [\"41398407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP188 encodes a large scaffold nucleoporin that forms a question mark-shaped keystone of the hetero-octameric inner ring of the nuclear pore complex (NPC), binding linker nucleoporins (Nic96/Nup145N/Nup53) through defined surface pockets to confer structural integrity and conformational plasticity to the NPC transport channel; beyond its NPC role, Nup188 binds FG-repeats and can translocate through NPCs like a transport receptor, directly interacts with Cep152 at the pericentriolar material to support centriole duplication, localizes to spindle poles via its C-terminus and recruits NuMA to promote chromosome alignment and K-fiber formation in mitosis, assists Nup93 in tethering and repressing HOXA gene loci at the nuclear periphery, and is required for left-right body patterning through a cilia-related mechanism.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Yeast Nup188p was identified as a major constituent of the NPC, localizing to both cytoplasmic and nucleoplasmic faces of the NPC core. It physically interacts with the pore membrane protein Pom152p and the nucleoporin Nic96p. Null mutants appear normal, but certain dominant alleles cause NPC-associated nuclear envelope herniations and growth inhibition at 37°C. Depletion of Pom152p in nup188 null cells causes severe nuclear envelope deformations, establishing Nup188p as part of the octagonal core structure involved in NPC structural organization.\",\n      \"method\": \"Immunoelectron microscopy, immunofluorescence, co-fractionation with isolated NPCs, genetic interaction analysis (synthetic lethality), dominant allele phenotypic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-fractionation, IEM localization, genetic epistasis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"8682855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminal domain of Nic96p functionally interacts with Nup188p in an allele-specific fashion; affinity purification of ProtA-Nup188p co-precipitated a fraction of Nic96p, establishing a physical interaction. Thermosensitive Nic96p mutations in its central domain inhibit NPC formation, and null mutants of NUP188 exhibit striking abnormalities in nuclear envelope and NPC morphology, placing Nup188p in the Nic96p-anchored structural network of the NPC.\",\n      \"method\": \"Allele-specific genetic interaction analysis, affinity purification (ProtA-Nup188p), electron microscopy of nuclear envelope morphology\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal physical interaction confirmed by affinity purification plus genetic epistasis with defined morphological readout\",\n      \"pmids\": [\"8682854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Genetic interaction screens in yeast revealed that deletion of NUP188 alone is not lethal, but pairwise deletion combinations with POM152 or NUP170 are synthetically lethal, and NUP188 was identified as a major component comprising over one-fifth of the mass of the isolated yeast NPC together with Nup170p, Nup157p, Pom152p, and Nic96p.\",\n      \"method\": \"Synthetic lethal screen, direct microsequencing of NPC-enriched fractions, genetic complementation analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical isolation plus genetic epistasis, replicated across two complementary approaches\",\n      \"pmids\": [\"8522578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Deletion of NUP188 (nup188-Δ) in yeast significantly increases passive nuclear envelope permeability: passive export rates of NLS-GFP reporters are faster, and equilibrium sieving limits for the NPC diffusion channel are larger than wild-type. This establishes Nup188p (together with Nup170p) as a determinant of the functional resting diameter of the NPC's central transport channel.\",\n      \"method\": \"In vivo fluorescence microscopy using NLS-GFP and NES-GFP reporters of varying sizes in nup188-Δ cells, passive diffusion measurements\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with quantitative in vivo transport assay and size-sieving readout\",\n      \"pmids\": [\"10831607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Elevated levels of Ssa1p (but not Ssb1p) suppress the NLS-GFP nuclear localization defects of nup188-Δ cells, placing Nup188p functionally upstream of Hsp70-assisted NLS-directed import. The differential suppression mapped to the nuclear export signal (NES) of Ssb1p, not to ATPase or peptide-binding domain differences, demonstrating a specific functional connection between Nup188p and cytosolic Hsp70 in nuclear transport.\",\n      \"method\": \"Genetic suppression analysis in nup188-Δ yeast, GFP reporter localization, chimeric Hsp70 constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined transport readout, single lab\",\n      \"pmids\": [\"10347213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"N-Nup145p (the GLFG-containing N-terminal cleavage product of Nup145p) becomes essential in a nup188 mutant background, demonstrating a synthetic lethal genetic interaction. Generation of the free N-domain by in vivo cleavage is required to complement this interaction, placing Nup188p in a functional network with GLFG-nucleoporins at the NPC.\",\n      \"method\": \"Synthetic lethality analysis in nup188 mutant background, domain complementation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined domain requirement, single study\",\n      \"pmids\": [\"9305650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Vertebrate Nup188 was identified using an organelle trap assay in Xenopus egg extracts. Xenopus Nup188 exists in a stable complex with xNup93 and xNup205, does not bind WGA directly but associates indirectly via N-acetylglucosamine-modified nucleoporins, and can assemble into annulate lamellae (a cytoplasmic NPC mimic). Human NUP188 was also identified as an ortholog.\",\n      \"method\": \"Organelle trap assay (affinity selection on WGA-Sepharose + in vitro annulate lamellae assembly), co-immunoprecipitation, biotinylation tagging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical reconstitution in Xenopus extract with in vitro pore assembly plus co-purification, multiple orthogonal methods\",\n      \"pmids\": [\"11029043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of yeast Nup188 was determined, revealing an extended stack of helices where the N-terminal ~130 kDa segment forms an intricate closed ring and the C-terminal region is a superhelical structure with distant similarity to S-shaped nuclear transport receptors (NTRs). Both Nup188 and Nup192 specifically bind FG-repeats and can translocate through NPCs by facilitated diffusion, blurring the distinction between stationary scaffold nucleoporins and soluble NTRs.\",\n      \"method\": \"X-ray crystallography (structure determination), FG-repeat binding assays, in vivo NPC translocation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro FG-repeat binding and in vivo translocation assays, multiple orthogonal methods\",\n      \"pmids\": [\"23795296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human Nup188 localizes to spindle poles during mitosis through its C-terminal region. Depletion of Nup188 causes failure of chromosome alignment at the metaphase plate, mitotic arrest via the spindle assembly checkpoint, and loss of robust K-fiber formation. Nup188 physically interacts with NuMA, and NuMA localization to spindle poles is perturbed in Nup188-depleted cells, establishing a mitotic function for Nup188 in chromosome segregation via K-fiber formation and NuMA recruitment.\",\n      \"method\": \"RNAi knockdown with live-cell imaging, immunofluorescence for spindle pole localization, co-immunoprecipitation (Nup188-NuMA interaction), spindle assembly checkpoint analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype plus co-IP and domain-mapping, multiple orthogonal methods\",\n      \"pmids\": [\"23551833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nup188 (together with Nup205) assists Nup93 in mediating repression of the HOXA gene cluster at the nuclear periphery. Depletion of the Nup93 sub-complex (Nup93/Nup188/Nup205) significantly upregulates HOXA gene expression, disengages the HOXA locus from the nuclear periphery (by 3D-FISH), increases active histone marks (H3K9ac), decreases repressive marks (H3K27me3), and increases transcription elongation marks (H3K36me3) on HOXA1.\",\n      \"method\": \"siRNA knockdown, ChIP, 3D-FISH, histone mark analysis by ChIP, RT-qPCR for gene expression\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, 3D-FISH, histone marks), single lab\",\n      \"pmids\": [\"27980680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GLFG repeats of Nup116 function redundantly with Nup188, a nonessential scaffold nucleoporin, to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly. Direct in vitro binding between GLFG-containing FG repeats and multiple scaffold Nups including Nup188 was demonstrated, revealing a structural 'Velcro' role for natively unfolded FG repeats in linking NPC subcomplexes.\",\n      \"method\": \"In vitro binding assays (FG-repeat/scaffold interaction), genetic epistasis (nup116Δ nup188 double mutants), in vivo NPC assembly assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstitution of FG-repeat binding plus genetic epistasis, replicated with multiple scaffold Nups\",\n      \"pmids\": [\"29033133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In budding yeast, Brl1 interacts with Nup188 by co-immunoprecipitation and with NPC components by split-YFP analysis. Brr6/Brl1 associate transiently with NPC assembly sites and promote NPC biogenesis; depletion causes NPC biogenesis defects while assembled NPCs remain intact, placing Nup188 within the Brl1-dependent NPC assembly pathway.\",\n      \"method\": \"Co-immunoprecipitation, split-YFP interaction analysis, conditional degron depletion, fluorescence microscopy of NPC assembly\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus split-YFP plus functional degron depletion, single lab\",\n      \"pmids\": [\"29439116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Quantitative fluorescence microscopy (NuRIM) revealed that Nup188 and its paralog Nup192 form a paralog pair whose altered expression leads to significant changes in NPC stoichiometry: overexpression of one leads to substitution for the other, revealing compositional plasticity at the NPC inner ring.\",\n      \"method\": \"Quantitative fluorescence microscopy (NuRIM), genetic manipulation of Nup188/Nup192 expression levels\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative imaging with functional manipulation, single lab\",\n      \"pmids\": [\"29632211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TDP-43 controls mRNA splicing of NUP188; complete knockout of TDP-43 in human cells results in aberrant Nup188 mRNA splicing, and this is accompanied by nuclear envelope morphological defects, establishing TDP-43 as a trans-acting splicing regulator of NUP188.\",\n      \"method\": \"TDP-43 knockout cell lines, transcriptomic analysis, RT-PCR validation of splicing defects, cell biological analysis of nuclear envelope morphology\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with transcriptomic and direct splicing validation, single lab\",\n      \"pmids\": [\"31527135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nup188 populates centrosomes (pericentriolar material, PCM) with newly synthesized protein that does not exchange with NPCs even after mitotic NPC breakdown. The PCM pool is subject to proteasomal degradation while the NPC pool is not, establishing differential turnover as a mechanism segregating Nup188 between the two compartments. Nup188 directly binds Cep152 and functions in centriole duplication at or upstream of Sas6 loading, linking its centrosomal role to congenital heart disease mechanisms.\",\n      \"method\": \"Pulse-chase fluorescent labeling, proximity-labeling (BioID), super-resolution microscopy, proteasome inhibitor experiments, direct binding assay (Nup188-Cep152), Nup188 depletion with Sas6 loading assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods (pulse-chase, BioID, super-resolution, direct binding, functional depletion), single lab but comprehensive\",\n      \"pmids\": [\"32211895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM and crystal structures of intact Nup188 (and Nup192) scaffold hubs bound to linker nucleoporin binding regions (Nic96, Nup145N, Nup53) were determined, revealing Nup188 as a question mark-shaped keystone of two evolutionarily conserved hetero-octameric inner ring complexes. Linkers bind to scaffold surface pockets through short defined motifs. Quantitative docking into cryo-ET maps of constricted and dilated NPCs positioned Nup188 in the intact fungal and human NPC and revealed that the linker-scaffold network allows inner ring constriction/dilation while outer ring spokes are cross-link stapled and restricted from dilation.\",\n      \"method\": \"Single-particle cryo-EM, X-ray crystallography, biochemical reconstitution, cryo-ET docking, structure-guided mutagenesis in S. cerevisiae\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple high-resolution structures combined with biochemical reconstitution and in vivo functional validation, comprehensive study\",\n      \"pmids\": [\"35679425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUP188 was identified as a Nesprin-2-interacting partner of the LINC complex at the nuclear envelope. Cytosol-localized SV40 polyomavirus is targeted to the nuclear envelope via Nesprin-2, which positions NUP188/NPC to capture the virus and facilitate nuclear translocation. This defines NUP188 as a physical bridge between the LINC complex and NPC for cargo handoff.\",\n      \"method\": \"Co-immunoprecipitation (Nesprin-2/NUP188 interaction), siRNA knockdown with viral infection assays, fluorescence microscopy tracking of SV40 nuclear entry\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP interaction plus functional knockdown with defined viral entry readout, single lab\",\n      \"pmids\": [\"36067270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Morpholino knockdown of NUP188 in Xenopus strongly disrupts both morphological left-right (LR) development and expression of pitx2, a molecular marker of LR patterning, identifying NUP188 as a gene required for LR body patterning, likely through a cilia-related mechanism at the gastrocoel roof plate LR organizer.\",\n      \"method\": \"Morpholino knockdown in Xenopus, in situ hybridization for pitx2 expression, morphological scoring of LR defects\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — morpholino KD with molecular and morphological readouts in model organism, part of a broader validated screen\",\n      \"pmids\": [\"21282601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A cold-sensitive nup188-brr7 allele causes defects in select protein import pathways as well as mRNA export in S. cerevisiae, linking Nup188 function specifically to nucleocytoplasmic transport through the Nic96 nucleoporin complex.\",\n      \"method\": \"Genetic screen (cold-sensitive mRNA export), dT50 in situ hybridization for poly-A RNA export, protein import assays in nup188 mutant\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific genetic and transport functional analysis, single lab\",\n      \"pmids\": [\"30021831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A genome-wide screen in yeast identified Nup188 as required for break-induced replication (BIR) completion, acting later than Nup84. Nup188 functions after DNA synthesis to support BIR repair completion, placing it sequentially in the BIR pathway distinct from its NPC structural role.\",\n      \"method\": \"Genome-wide genetic screen for BIR deficiency, validation by epistasis analysis of nup188 deletion in BIR assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen with targeted validation and epistasis placement, single study\",\n      \"pmids\": [\"41398407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Full-length Pom152p (including its lumenal C-terminal domain) is required to rescue nup188 mutations, while the N-terminal domain alone can rescue nic96 and nup59 mutants, demonstrating that Nup188p's functional interaction with Pom152p requires the lumenal structures of Pom152p and implicating the pore membrane-to-scaffold connection in NUP188 function.\",\n      \"method\": \"Domain complementation assays of Pom152p in nup188 and other nup mutant backgrounds, topology mapping by alkaline extraction and protease protection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic domain complementation in defined genetic backgrounds, single lab\",\n      \"pmids\": [\"9988776\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP188 encodes a large scaffold nucleoporin that forms a question mark-shaped keystone of the NPC inner ring, interacting physically with Nic96/Nup93, Pom152, Nup205, and linker nucleoporins to establish the NPC's structural integrity and central transport channel diameter; beyond its NPC role, Nup188 localizes to the pericentriolar material where it directly binds Cep152 to promote centriole duplication, localizes to spindle poles to recruit NuMA and facilitate K-fiber formation during mitosis, assists Nup93 in tethering and repressing the HOXA gene cluster at the nuclear periphery, functions in left-right body patterning via cilia-related mechanisms, and binds FG-repeats through an NTR-like fold allowing it to translocate through NPCs by facilitated diffusion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP188 encodes a large scaffold nucleoporin that forms a question mark-shaped keystone of the hetero-octameric inner ring complex of the nuclear pore complex (NPC), binding linker nucleoporins Nic96, Nup145N, and Nup53 through defined surface pockets to confer structural integrity and conformational plasticity to the transport channel [PMID:35679425, PMID:8682855]. Loss of Nup188 increases the passive permeability of the NPC diffusion barrier and impairs select protein import and mRNA export pathways, while its structural similarity to nuclear transport receptors enables it to bind FG-repeats and translocate through NPCs by facilitated diffusion [PMID:10831607, PMID:23795296, PMID:30021831]. Beyond its NPC role, Nup188 directly binds Cep152 at the pericentriolar material to promote centriole duplication, localizes to spindle poles during mitosis where it recruits NuMA to support K-fiber formation and chromosome alignment, and participates with Nup93 in tethering and repressing HOXA gene loci at the nuclear periphery [PMID:32211895, PMID:23551833, PMID:27980680]. Nup188 is also required for left-right body patterning in Xenopus, functioning late in break-induced replication in yeast, and displaying compositional plasticity with its paralog Nup192 at the NPC [PMID:21282601, PMID:41398407, PMID:29632211].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that Nup188 belongs to a functionally interdependent group of NPC scaffold components: synthetic lethal interactions between NUP188, POM152, and NUP170 deletions demonstrated that these nucleoporins constitute a major structural unit of the NPC.\",\n      \"evidence\": \"Systematic pairwise gene deletion and synthetic lethal screening in S. cerevisiae\",\n      \"pmids\": [\"8522578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular contacts between Nup188 and Nup170/Pom152 were not mapped\", \"No structural information on Nup188 itself\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defining the physical interactions and NPC localization of Nup188: immunoelectron microscopy placed Nup188 on both faces of the NPC core, and affinity purification identified direct interactions with Nic96 and Pom152, establishing Nup188 as a core NPC scaffold component.\",\n      \"evidence\": \"ImmunoEM, affinity purification of ProtA-Nup188p, genetic epistasis with dominant alleles in S. cerevisiae\",\n      \"pmids\": [\"8682855\", \"8682854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of Nup188 within the NPC was unknown\", \"Structural basis of the Nic96–Nup188 interaction was unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Placing Nup188 in a functional pathway with the FG-nucleoporin Nup145N: the N-terminal GLFG domain of Nup145p became essential in a nup188 mutant background, and in vivo cleavage to generate the free N-domain was required for complementation, linking FG-repeat function to Nup188-dependent NPC scaffold integrity.\",\n      \"evidence\": \"Genetic epistasis, synthetic lethality complementation with domain truncations in S. cerevisiae\",\n      \"pmids\": [\"9305650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Nup188 directly binds FG-repeats was untested\", \"Mechanism by which N-Nup145p compensates for Nup188 loss was unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that Nup188 controls the NPC permeability barrier: deletion of NUP188 increased passive diffusion rates and expanded the functional sieving limit of the NPC channel, establishing a direct role in setting the resting transport channel diameter.\",\n      \"evidence\": \"In vivo GFP reporter passive transport assay in nup188Δ yeast\",\n      \"pmids\": [\"10831607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the permeability defect reflects altered FG-repeat organization or structural widening was unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying the vertebrate Nup188 and its complex partners: Xenopus/human Nup188 was cloned and shown to reside in a complex with Nup93 and Nup205, extending the yeast scaffold organization to metazoans.\",\n      \"evidence\": \"Organelle trap assay with WGA-Sepharose, co-complex identification from Xenopus egg extracts\",\n      \"pmids\": [\"11029043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct pairwise binding within the Nup93–Nup188–Nup205 complex was not dissected\", \"Functional role of vertebrate Nup188 was untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealing a developmental role for NUP188 in left-right body patterning: morpholino knockdown in Xenopus disrupted pitx2 expression and LR morphology, establishing NUP188 as required for an embryonic patterning process linked to cilia function.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus embryos, in situ hybridization, morphological scoring\",\n      \"pmids\": [\"21282601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the LR defect is NPC-dependent or reflects a cilia-specific function was unknown\", \"Mammalian validation was lacking\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovering mitotic functions for Nup188 at the spindle pole: human Nup188 localizes to spindle poles via its C-terminus, directly binds NuMA, and its depletion causes chromosome alignment failure and K-fiber defects, establishing a non-NPC mitotic role.\",\n      \"evidence\": \"siRNA knockdown, co-immunoprecipitation (Nup188–NuMA), live/fixed imaging in human cells\",\n      \"pmids\": [\"23551833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mitotic pool is distinct from the NPC pool was unknown\", \"Mechanism of Nup188 recruitment to spindle poles was not fully defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolving the structural architecture and NTR-like properties of Nup188: crystal structure revealed an extended helical scaffold with a closed N-terminal ring and a C-terminal superhelix resembling nuclear transport receptors; Nup188 binds FG-repeats and translocates through NPCs by facilitated diffusion.\",\n      \"evidence\": \"X-ray crystallography, in vitro FG-repeat binding, NPC translocation assay\",\n      \"pmids\": [\"23795296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of NTR-like translocation was unclear\", \"Whether FG-repeat binding contributes to NPC assembly or transport regulation was unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending Nup188 function to gene regulation: as part of the Nup93 sub-complex, Nup188 helps tether HOXA loci to the nuclear periphery and maintain repressive chromatin marks, with depletion causing locus detachment and transcriptional derepression.\",\n      \"evidence\": \"ChIP, 3D-FISH, histone mark analysis, siRNA knockdown in human cells\",\n      \"pmids\": [\"27980680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Nup188 contacts chromatin directly or acts only through Nup93 was unresolved\", \"Genome-wide scope of Nup188-dependent gene regulation was not assessed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing that FG-repeat binding to Nup188 is functionally relevant for NPC assembly: GLFG repeats of Nup116 function redundantly with Nup188 to stabilize scaffold interactions during late NPC assembly steps, and direct binding was confirmed in vitro.\",\n      \"evidence\": \"In vitro FG-repeat binding assay, yeast double-mutant genetic analysis\",\n      \"pmids\": [\"29033133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FG-repeat–Nup188 interaction was not determined at atomic resolution\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating compositional plasticity between Nup188 and its paralog Nup192: quantitative fluorescence microscopy showed that altered expression of one paralog induces stoichiometric substitution at the NPC, revealing that the inner ring can tolerate compositional variation.\",\n      \"evidence\": \"Quantitative fluorescence microscopy (NuRIM pipeline) in budding yeast\",\n      \"pmids\": [\"29632211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of paralog substitution on transport selectivity were not tested\", \"Whether this plasticity occurs in metazoan NPCs was unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovering a dedicated centrosomal role for Nup188 in centriole duplication: newly synthesized Nup188 populates centrosomes as a distinct pool that does not exchange with NPCs, directly binds Cep152, and functions at or upstream of Sas6 loading, establishing a bona fide non-NPC function at the pericentriolar material.\",\n      \"evidence\": \"Pulse-chase labeling, BioID proximity labeling, direct binding assay, super-resolution microscopy, loss-of-function centriole duplication assay in human cells\",\n      \"pmids\": [\"32211895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Nup188 promotes Sas6 loading was not elucidated\", \"Regulation of the NPC vs. centrosomal pool sorting was not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Determining the high-resolution composite structure of the Nup188-containing inner ring complex: crystal and cryo-EM structures of Nup188 bound to linker nucleoporins revealed the hetero-octameric inner ring architecture, with cryo-ET docking showing how eight rigid spokes with flexible interconnections enable NPC dilation and constriction.\",\n      \"evidence\": \"Crystal structure, single-particle cryo-EM, cryo-ET docking, structure-guided mutagenesis in S. cerevisiae\",\n      \"pmids\": [\"35679425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of spoke rearrangement during active transport were not captured\", \"Whether post-translational modifications regulate linker–scaffold interactions was untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicating Nup188 in DNA repair: a genome-wide screen identified Nup188 as functioning in a late step of break-induced replication, after the Nup84-dependent early step, placing inner ring nucleoporins in sequential NPC-dependent DNA repair.\",\n      \"evidence\": \"Genome-wide genetic screen, BIR assay, epistasis analysis in S. cerevisiae\",\n      \"pmids\": [\"41398407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Nup188 supports late BIR steps is unknown\", \"Whether Nup188's role in BIR is through transport gating or direct DNA interaction is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how the NPC, centrosomal, and chromatin-associated pools of Nup188 are differentially regulated, whether Nup188's NTR-like FG-repeat binding serves a cargo-transport function in vivo, and the molecular mechanism linking Nup188 to left-right patterning and cilia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo cargo for the NTR-like translocation activity has been identified\", \"Mechanism connecting Nup188 to cilia function and LR patterning is uncharacterized\", \"Post-translational regulation of pool sorting (NPC vs. centrosome) is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7, 17]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 12, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"NPC inner ring complex (Nup93 sub-complex)\",\n      \"Nup93-Nup188-Nup205 complex\"\n    ],\n    \"partners\": [\n      \"NUP93\",\n      \"NIC96\",\n      \"NUP205\",\n      \"POM152\",\n      \"NUP145N\",\n      \"NUMA1\",\n      \"CEP152\",\n      \"BRL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP188 encodes a large scaffold nucleoporin that serves as a question-mark-shaped keystone of the nuclear pore complex (NPC) inner ring, where it establishes structural integrity, sets the resting diameter of the central transport channel, and enables NPC constriction–dilation dynamics through a linker–scaffold network with Nic96/Nup93, Nup205, Pom152, and linker nucleoporins [PMID:8682855, PMID:10831607, PMID:35679425]. Its NTR-like fold binds FG-repeat domains and allows facilitated diffusion through the NPC, blurring the classical distinction between stationary scaffold and mobile transport factors [PMID:23795296, PMID:29033133]. Beyond the NPC, NUP188 localizes to centrosomes where it directly binds Cep152 to promote centriole duplication, to mitotic spindle poles where it recruits NuMA for K-fiber formation, and to the nuclear periphery where it participates with Nup93 in HOXA gene cluster repression [PMID:32211895, PMID:23551833, PMID:27980680]. NUP188 is also required for left–right body axis patterning in Xenopus, likely via cilia-dependent signaling [PMID:21282601].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The initial question—what are the principal mass components of the NPC scaffold?—was addressed by direct microsequencing of isolated yeast NPCs, which identified Nup188 as constituting a major fraction of total NPC mass and revealed synthetic lethal interactions with POM152 and NUP170, establishing Nup188 within a redundant structural scaffold network.\",\n      \"evidence\": \"Microsequencing of purified yeast NPC fractions combined with synthetic lethal screens in S. cerevisiae\",\n      \"pmids\": [\"8522578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise stoichiometry and position of Nup188 within the NPC were not resolved\", \"Vertebrate ortholog was not yet identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The question of where Nup188 sits within the NPC and which partners anchor it was resolved by immuno-EM localizing Nup188 to both faces of the NPC core and by demonstrating direct physical interactions with Nic96p and Pom152p, defining the inner-ring Nic96–Nup188 axis as a central organizational module.\",\n      \"evidence\": \"Immuno-electron microscopy, affinity purification (ProtA-Nup188p), allele-specific genetic interaction analysis in S. cerevisiae\",\n      \"pmids\": [\"8682855\", \"8682854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Nic96–Nup188 interaction was unknown\", \"Contribution of Nup188 to transport selectivity was not measured\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The functional requirement for the Pom152 lumenal domain in rescuing nup188 mutations, and the genetic connection between Nup188 deletion and Hsp70-assisted import, together established that Nup188 functionally bridges the pore membrane and the transport machinery.\",\n      \"evidence\": \"Domain complementation assays of Pom152 in nup188 mutant backgrounds; genetic suppression of nup188Δ import defects by Ssa1p overexpression in S. cerevisiae\",\n      \"pmids\": [\"9988776\", \"10347213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface between Nup188 and the Pom152 lumenal domain was not mapped\", \"Mechanism by which Hsp70 suppresses nup188Δ transport defects was not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The question of whether Nup188 has a functional role in transport selectivity—beyond passive scaffolding—was answered: nup188Δ cells show an enlarged NPC diffusion channel, demonstrating that Nup188 is a determinant of the NPC's size-exclusion barrier.\",\n      \"evidence\": \"Quantitative in vivo fluorescence transport assays with NLS/NES-GFP reporters of varying sizes in nup188Δ S. cerevisiae; identification of vertebrate Nup188 in Xenopus extract NPC assemblies\",\n      \"pmids\": [\"10831607\", \"11029043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Nup188 physically restricts channel diameter was structurally undefined\", \"Vertebrate Nup188 function in transport had not been tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether NUP188 functions outside nucleocytoplasmic transport was an open question; morpholino knockdown in Xenopus revealed a requirement for NUP188 in left–right body patterning, likely via cilia at the gastrocoel roof plate, extending NUP188 biology to developmental signaling.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus embryos with pitx2 in situ hybridization and LR morphological scoring\",\n      \"pmids\": [\"21282601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ciliary localization of Nup188 in the LR organizer was not shown\", \"Whether the phenotype is NPC-dependent or NPC-independent was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two landmark studies resolved the structure and an unexpected NPC-external function: the crystal structure revealed an NTR-like fold that binds FG-repeats and enables NPC translocation, while RNAi in human cells showed spindle-pole localization during mitosis with NuMA recruitment enabling K-fiber formation—establishing Nup188 as both a scaffold and a mobile, multifunctional protein.\",\n      \"evidence\": \"X-ray crystallography of yeast Nup188 with FG-repeat binding and in vivo translocation assays; RNAi knockdown with live-cell imaging, co-IP (Nup188–NuMA), and K-fiber analysis in human cells\",\n      \"pmids\": [\"23795296\", \"23551833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of full-length vertebrate NUP188 was lacking\", \"Whether mitotic and interphase pools are independently regulated was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that depletion of Nup188 (as part of the Nup93 sub-complex) derepresses the HOXA gene cluster and displaces it from the nuclear periphery established a chromatin-regulatory role, answering whether inner-ring nucleoporins participate in gene silencing.\",\n      \"evidence\": \"siRNA knockdown with ChIP for histone marks, 3D-FISH for locus positioning, RT-qPCR in human cells\",\n      \"pmids\": [\"27980680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Nup188 contributes independently of Nup93 to HOXA repression was not isolated\", \"Genome-wide scope of Nup188 chromatin regulation was not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Multiple studies consolidated the NPC assembly and transport roles: FG-repeat 'Velcro' linkages with Nup188 stabilize late NPC assembly, Brl1 transiently recruits Nup188 during NPC biogenesis, compositional plasticity between Nup188 and Nup192 was quantified, and a cold-sensitive allele linked Nup188 to both protein import and mRNA export pathways.\",\n      \"evidence\": \"In vitro FG-repeat binding plus genetic epistasis (Cell); co-IP and split-YFP with Brl1 (JCB); quantitative fluorescence NuRIM (PNAS); cold-sensitive allele transport assays (G3), all in S. cerevisiae\",\n      \"pmids\": [\"29033133\", \"29439116\", \"29632211\", \"30021831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal order of scaffold assembly involving Nup188 was not fully resolved\", \"Whether Nup188/Nup192 plasticity exists in metazoans was not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The centrosomal function of Nup188 was mechanistically dissected: newly synthesized Nup188 populates the pericentriolar material independently of NPC pools, directly binds Cep152, and is required for Sas6 loading during centriole duplication, with differential proteasomal degradation segregating centrosomal and NPC pools.\",\n      \"evidence\": \"Pulse-chase fluorescent labeling, BioID proximity labeling, super-resolution microscopy, direct binding assays (Nup188–Cep152), Sas6 loading assays upon Nup188 depletion in human cells\",\n      \"pmids\": [\"32211895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Nup188–Cep152 binding was not determined\", \"Whether the centrosomal pool contributes to congenital heart disease mechanisms in vivo remains to be established in animal models\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"High-resolution cryo-EM structures of Nup188 bound to linker nucleoporins defined it as the question-mark-shaped keystone of two hetero-octameric inner-ring complexes, and docking into cryo-ET maps of constricted/dilated NPCs explained how the linker–scaffold network permits inner-ring dilation; separately, Nup188 was shown to bridge the LINC complex (Nesprin-2) to the NPC for SV40 virus nuclear entry.\",\n      \"evidence\": \"Single-particle cryo-EM and X-ray crystallography with cryo-ET docking and structure-guided mutagenesis in S. cerevisiae (Science); co-IP and siRNA knockdown with viral infection assays in human cells (PLoS Pathog)\",\n      \"pmids\": [\"35679425\", \"36067270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full in situ structure of the human NPC inner ring at atomic resolution was not achieved\", \"Generality of the LINC–NPC handoff to non-viral cargoes was untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A genome-wide screen identified Nup188 as required for break-induced replication (BIR) completion at a step after DNA synthesis, expanding its roles to DNA repair and placing it sequentially downstream of the Nup84 outer-ring complex in BIR.\",\n      \"evidence\": \"Genome-wide genetic screen for BIR deficiency with epistasis validation in S. cerevisiae\",\n      \"pmids\": [\"41398407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which Nup188 supports BIR completion is unknown\", \"Whether this reflects a transport-dependent or NPC-tethering-dependent role was not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the atomic-resolution in situ architecture of metazoan NPC inner rings containing NUP188, (2) the structural basis of Nup188's centrosomal interactions and whether centriole duplication defects underlie congenital heart disease in vivo, (3) whether chromatin-regulatory and BIR functions are NPC-scaffold-dependent or reflect moonlighting of soluble Nup188 pools, and (4) the mechanism linking NUP188 to left–right patterning.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in situ atomic-resolution metazoan NPC structure with NUP188 resolved\", \"Centrosomal function not validated in animal disease models\", \"Chromatin and BIR mechanisms not dissected from NPC transport functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 6, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 6, 15, 16]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [10, 11, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"NPC inner ring complex (Nup93 sub-complex)\",\n      \"Nup93–Nup188–Nup205 complex\"\n    ],\n    \"partners\": [\n      \"NUP93\",\n      \"NUP205\",\n      \"POM152\",\n      \"NIC96\",\n      \"NUMA1\",\n      \"CEP152\",\n      \"SYNE2\",\n      \"BRL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}