{"gene":"SEC13","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2006,"finding":"Sec13 and Sec31 form a 2:2 heterotetramer that self-assembles into cuboctahedral cage structures in the absence of Sec23/24, revealing that Sec13/31 has a primary structural role in COPII coat formation. Cryo-EM reconstruction at 30 Å resolution showed a novel cuboctahedron geometry capable of forming a flexible lattice.","method":"Cryo-electron microscopy and single particle analysis of purified Sec13/31 cages","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural reconstruction with in vitro reconstitution of self-assembled cages, foundational structural result independently confirmed by subsequent studies","pmids":["16407955"],"is_preprint":false},{"year":2010,"finding":"The COPII accessory protein Sec16 contains an ACE1 (ancestral coatomer element 1) domain and forms a 2:2 tetramer edge element with Sec13, analogous to the Sec13-Sec31 edge element. Crystal structure at 2.7 Å resolution showed domain swapping at the ACE1-ACE1 interface; in vivo data indicated the ACE1 of Sec31 can functionally replace the ACE1 of Sec16, supporting Sec16 as a scaffold/template for COPII coat assembly.","method":"X-ray crystallography (2.7 Å crystal structure of Sec16 central domain–Sec13 complex), in vivo complementation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with in vivo functional validation, multiple orthogonal methods in one study","pmids":["20696705"],"is_preprint":false},{"year":2009,"finding":"Sec13 participates in the nuclear pore complex (NPC) Y-complex as a structural component forming a heterotrimeric edge element with Nup84 and Nup145C. Crystal structure of the 134-kDa Nup84-Nup145C-Sec13 complex showed that the heterotypic ACE1 interaction of Nup84 and Nup145C is analogous to the homotypic ACE1 interaction of Sec31 in COPII, supporting a common lattice architecture between COPII and NPC scaffolds.","method":"X-ray crystallography of Nup84-Nup145C-Sec13 complex","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with molecular modeling of Y complex, orthologous confirmation of shared ACE1 architecture","pmids":["19855394"],"is_preprint":false},{"year":2003,"finding":"Human Sec13 directly interacts with Nup96 at the nuclear pore complex via the WD repeat region of Sec13 and the N-terminal region of Nup96. Sec13 shuttles between intranuclear sites and cytoplasm (shown by FRAP), a fraction is stably associated with NPCs during interphase, and Sec13 contains a nuclear localization signal enabling active nuclear import.","method":"Yeast two-hybrid, biochemical co-immunoprecipitation, immunofluorescence/confocal/immunoelectron microscopy, photobleaching (FRAP), cotransfection competition assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, FRAP, multiple imaging modalities, functional in vivo competition experiment confirming interaction","pmids":["14517296"],"is_preprint":false},{"year":2008,"finding":"Sec13 depletion causes concomitant loss of Sec31 and juxtanuclear clustering of Sec23/24-containing pre-budding complexes. Sec13/31 is not required for generation of membrane curvature at the ER (curved coated profiles persist), but efficient coupling of the inner (Sec23/24) and outer (Sec13/31) COPII layers is specifically required for collagen export from the ER in primary fibroblasts, while general secretory cargo (tsO45-G-YFP) export is unaffected.","method":"siRNA knockdown, electron microscopy, live-cell fluorescence imaging, secretion assays in primary fibroblasts, zebrafish morpholino knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, live imaging, functional secretion assays) in cell and in vivo models, result replicated across systems","pmids":["18713835"],"is_preprint":false},{"year":2014,"finding":"The nuclear pore function of Sec13 (distinct from its COPII function) is specifically required for retinal development. Loss of COPII function (sec31a/b knockdown or brefeldin A) did not cause retinal lamination defects, while sec13 mutation caused NPC failure, nuclear mRNA accumulation, and p53-dependent apoptosis in retinal cells. The retinal phenotype was phenocopied by loss of NPC-specific component Nup107.","method":"Zebrafish genetic model (sec13 sq198 mutant), morpholino knockdown of sec31a/sec31b, brefeldin A treatment, nuclear mRNA localization assay, apoptosis assay, genetic epistasis with nup107 knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple controls distinguishing COPII vs. NPC function, phenocopy by NPC-specific component, multiple orthogonal experiments in one study","pmids":["24627485"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, a C-terminal truncation of Sec13 that loses affinity for Sec31a leads to ER structural disintegration in differentiated cells (chondrocytes, intestinal epithelial cells, hepatocytes), triggering unfolded protein response, cell-cycle arrest, and apoptosis, arresting digestive organ growth. This provides direct genetic evidence that COPII function is essential for digestive system organogenesis.","method":"Zebrafish genetic mutant analysis, co-immunoprecipitation (Sec13 truncation vs. Sec31a), electron microscopy of ER structure, UPR assays, apoptosis assays","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with biochemical validation of loss of Sec31a interaction, EM confirmation of ER structure, multiple cellular phenotype readouts","pmids":["22609279"],"is_preprint":false},{"year":2010,"finding":"p125A forms a stable ternary complex with Sec13/Sec31A in the cytosol, existing primarily as preassembled Sec13/Sec31A/p125A heterohexamers. p125A binds the C-terminal region of Sec31A (residues 260–600 of p125A) via a domain distinct from its Sec23A-binding domain. Loss of p125A disrupts Golgi morphology and ER protein export.","method":"Co-immunoprecipitation, gel filtration, immunodepletion, siRNA knockdown with ER export and Golgi morphology assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, gel filtration, domain mapping, and functional rescue, multiple orthogonal methods in single study","pmids":["20679433"],"is_preprint":false},{"year":2011,"finding":"Sec13 is a component of the SEA (Seh1-Associated) complex in yeast, which also contains Seh1, Npr2, Npr3, and Sea1–Sea4 proteins. SEA complex proteins share structural characteristics with COPI, COPII, NPC, and vesicle tethering complexes HOPS/CORVET. The SEA complex dynamically associates with the vacuole in vivo and has roles in intracellular trafficking, amino acid biogenesis, and nitrogen starvation response.","method":"Mass spectrometry proteomics, co-immunoprecipitation, computational structural modeling, yeast genetics/genetic assays, in vivo vacuole localization","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS proteomics, biochemical Co-IP, in vivo localization, and genetic assays all converging on SEA complex composition and function","pmids":["21454883"],"is_preprint":false},{"year":1998,"finding":"The conserved aspartic acid residues in WD repeat blades of Sec13 (yeast) are important but not individually essential for folding of the WD propeller structure. Mutating conserved Asp to Gly in individual blades of Sec13 affects folding in vitro and in COS-7 cells equally; double mutants fold poorly. The repeats most affecting folding differ between Sec13 and Gβ, indicating different folding pathways for different WD repeat proteins.","method":"Site-directed mutagenesis of conserved Asp residues, in vitro folding assay, expression in COS-7 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with in vitro and in vivo folding assays, single laboratory study","pmids":["9535892"],"is_preprint":false},{"year":2017,"finding":"TRAPPIII complex (via its specific subunit TRAPPC12) binds to the Sec13/Sec31A tetramer (but not to Sec13 or Sec31A alone) and positively modulates the assembly of the COPII outer layer during vesicle formation at ER exit sites. TRAPPC12 localizes to ER exit sites/ERGIC, and its deletion disperses the ERGIC and delays ER-to-Golgi transport.","method":"Co-immunoprecipitation, TRAPPC12 knockout/knockdown, ER-to-Golgi transport assay, immunofluorescence localization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defining binding requirement for tetramer, functional KO data, localization studies; single laboratory","pmids":["28240221"],"is_preprint":false},{"year":2018,"finding":"PAQR3 interacts with the WD domains of Sec13 and Sec31A (via its N-terminal end) and facilitates tethering of COPII vesicles to the Golgi. PAQR3 deletion delays ER-to-Golgi trafficking (assessed by BFA washout and RUSH assay). PAQR3 enhances Golgi localization of Sec13 and Sec31A.","method":"APEX2 proximity labeling, Co-immunoprecipitation, PAQR3 knockout, BFA washout assay, RUSH assay, domain mapping","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling, Co-IP domain mapping, KO with trafficking functional assay; single laboratory","pmids":["30466064"],"is_preprint":false},{"year":2024,"finding":"SPOP mediates K63-linked ubiquitination of Sec13, a component of the GATOR2 complex. K63-ubiquitination of Sec13 attenuates its interaction with other GATOR2 components, thereby suppressing GATOR2 activity and negatively regulating mTORC1 signaling in response to amino acids. SPOP deficiency promotes cancer cell proliferation/migration in a Sec13-dependent manner.","method":"Co-immunoprecipitation, ubiquitination assay (K63 linkage), Sec13 knockdown rescue experiment, mTORC1 activity assay, cell proliferation/migration assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination biochemistry, and genetic epistasis (SPOP KD rescued by Sec13 KD); single laboratory","pmids":["38242269"],"is_preprint":false},{"year":2022,"finding":"Sec13-dependent COPII protein trafficking is required for oligodendrocyte (OL) differentiation and myelination. Ablation of Sec13 in OL lineage prevents OPC differentiation and inhibits myelination/remyelination. Loss of Sec13 alters the OL secretome and specifically inhibits secretion of pleiotrophin (PTN), which acts as an autocrine factor promoting OL differentiation and myelin repair.","method":"Conditional Sec13 knockout in OL lineage, remyelination model, secretome analysis, PTN rescue experiments, COPII enhancer (TUDCA) treatment, ectopic COPII component expression","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype, secretome analysis identifying PTN, autocrine rescue experiment; single laboratory","pmids":["35143418"],"is_preprint":false},{"year":2000,"finding":"Mammalian Sec13 (mSec13p) directly binds rabphilin-11 in cell-free and intact cell systems. The interaction is enhanced by GTP-Rab11p. Disruption of the rabphilin-11–mSec13p interaction by overexpression of the mSec13p-binding domain of rabphilin-11 impairs vesicle trafficking in the perinuclear/Golgi region.","method":"Cell-free binding assay, co-immunoprecipitation from intact cells, immunofluorescence colocalization, dominant-negative overexpression of binding domain","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-free binding and Co-IP from cells, dominant-negative functional evidence; single laboratory","pmids":["10747849"],"is_preprint":false},{"year":2009,"finding":"Sec13 directly interacts with presenilin-1 (PS1); the interaction maps to the N-terminal part of the large hydrophilic PS1 cytoplasmic loop and the first WD40-repeat of Sec13.","method":"Pulldown/binding assay, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single interaction mapping study, limited functional follow-up described in abstract, single laboratory","pmids":["19682973"],"is_preprint":false},{"year":2018,"finding":"Sec13 functions as a positive regulator of VISA (MAVS)-mediated antiviral signaling. Sec13 specifically co-immunoprecipitates with VISA. Overexpression of Sec13 increases VISA aggregation and ubiquitination, enhances IRF3 phosphorylation and dimerization, and promotes IFN-β production. Knockdown of Sec13 attenuates Sendai virus-induced IRF3 activation and IFN-β production.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown, IRF3 phosphorylation/dimerization assays, IFN-β reporter/ELISA","journal":"Virus genes","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, gain- and loss-of-function with molecular pathway readouts; single laboratory","pmids":["29948782"],"is_preprint":false},{"year":2024,"finding":"Sec13 forms a protein complex with Pgm1 (phosphoglucomutase 1) and Ubqln1. Sec13 inhibits Ubqln1-mediated K48-linked ubiquitination and degradation of Pgm1, thereby stabilizing Pgm1 and promoting glycolysis (G6P and lactate production) in acute lung injury.","method":"Co-immunoprecipitation, ubiquitination assay, Sec13/Pgm1/Ubqln1 knockdown/overexpression, metabolite measurement (G6P, lactate)","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay with functional metabolic readouts, but single laboratory, limited mechanistic validation","pmids":["39159700"],"is_preprint":false},{"year":2018,"finding":"The C-terminal disordered region of Sec31 (residues 820–1220) regulates the flexibility and rigidity of Sec13/31 cages. Deletion of this region produces Sec13/31ΔC cages with more homogeneous size distribution but greater conformational heterogeneity within cuboctahedra. Cryo-EM and MD flexible fitting identified a new hinge for Sec31 β-propeller domain flexing and increased flexibility of a known hinge.","method":"Cryo-EM, biophysical characterization of purified complexes, molecular dynamics flexible fitting (MDFF)","journal":"Journal of structural biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural analysis with MD simulations, deletion mutant analysis; single laboratory","pmids":["30172710"],"is_preprint":false},{"year":2005,"finding":"Human Sec13 localizes to kinetochores at metaphase during mitosis. Overexpression of Sec13 causes cells to evade mitotic arrest in response to spindle damage (nocodazole), leading to G1-like phase and apoptotic cell death, and results in giant nuclei formation, suggesting a role in the metaphase/anaphase transition.","method":"GFP-tagging and live cell imaging, cell cycle analysis, nocodazole treatment, apoptosis assay","journal":"Experimental & molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single laboratory, GFP localization and overexpression with phenotypic readouts but no mechanistic pathway placement","pmids":["16000881"],"is_preprint":false},{"year":2011,"finding":"Calcineurin A (Cna1) physically associates with the COPII component Sec13 in Cryptococcus neoformans, as identified by quantitative mass spectrometry and confirmed by co-immunoprecipitation. Cna1 co-localizes with Sec13 at ER-associated puncta during high-temperature stress.","method":"Mass spectrometry from immunoprecipitation, co-immunoprecipitation, immunofluorescence colocalization","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP confirmation of MS hit, localization data, but no functional follow-up on the interaction mechanism; single laboratory, non-mammalian organism","pmids":["21984910"],"is_preprint":false},{"year":2023,"finding":"In euglenozoan protists (diplonemids), two Sec13 paralogues have functionally diverged: Sec13a interacts with COPII components and the NPC, while Sec13b interacts with Sec16 and SEA/GATOR complex components. This demonstrates that the three established Sec13 roles (COPII, NPC, SEA/GATOR) can be distributed across paralogues.","method":"Co-immunoprecipitation/protein interaction studies, subcellular localization imaging, yeast two-hybrid","journal":"Open biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction and localization data in a non-mammalian organism (diplonemid protist), single laboratory","pmids":["37311539"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, the Sec13 orthologue NPP-20 (a nucleoporin) is required for nuclear import of the centromeric protein HCP-4. Knockdown of NPP-20 causes HCP-4 to remain in the cytosol during prophase, preventing its incorporation into centromeres and causing chromosomal segregation defects.","method":"RNAi knockdown in C. elegans, immunofluorescence localization of HCP-4, chromosome segregation phenotype analysis","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNAi knockdown with localization and phenotypic readouts in C. elegans; NPP-20 is the SEC13 orthologue (alias confirmed) but functional follow-up is limited to localization","pmids":["28122936"],"is_preprint":false}],"current_model":"SEC13 is a WD40-repeat β-propeller protein that serves as a structural component in at least three distinct multi-protein complexes: (1) the COPII outer coat, where Sec13/Sec31 heterotetramers self-assemble into cuboctahedral cage lattices to drive ER-to-Golgi vesicle formation (with a specific requirement for large cargo such as collagen), (2) the nuclear pore complex Y-complex scaffold, where Sec13 forms an ACE1-based edge element with Nup84/Nup145C and stably interacts with Nup96 while also shuttling between nucleus and cytoplasm, and (3) the SEA/GATOR2 nutrient-sensing complex, where SPOP-mediated K63-ubiquitination of Sec13 attenuates GATOR2 integrity and suppresses mTORC1 signaling; additionally, Sec13 interacts with the COPII scaffold protein Sec16 via a second ACE1 edge element, is positively modulated in COPII outer-layer assembly by the TRAPPIII complex, and participates in VISA-mediated antiviral IFN-β signaling and autocrine pleiotrophin secretion required for oligodendrocyte myelination."},"narrative":{"mechanistic_narrative":"SEC13 is a WD40-repeat β-propeller protein that functions as a shared structural module across multiple multi-protein scaffolds, most prominently the COPII vesicle coat that drives ER-to-Golgi transport [PMID:16407955, PMID:18713835]. With Sec31 it forms a 2:2 heterotetramer that self-assembles into cuboctahedral cage lattices independently of the inner Sec23/24 layer, defining its primary role as an outer-coat structural element [PMID:16407955]; the C-terminal disordered region of Sec31 tunes the rigidity and conformational heterogeneity of these cages [PMID:30172710]. SEC13 contributes a recurring ACE1-based edge element: it pairs with the COPII scaffold Sec16 through domain-swapped ACE1–ACE1 interfaces [PMID:20696705], and an equivalent architecture builds the nuclear pore Y-complex, where SEC13 forms a heterotrimeric edge with Nup84 and Nup145C and stably binds Nup96, linking COPII and NPC scaffolds to a common lattice design [PMID:19855394, PMID:14517296]. These two activities are functionally separable: COPII-dependent SEC13 function is specifically required for export of large cargo such as collagen and for ER/digestive-organ and oligodendrocyte secretory biology [PMID:18713835, PMID:22609279, PMID:35143418], whereas its nuclear-pore function supports nucleocytoplasmic transport and is selectively required for retinal development [PMID:24627485]. SEC13 is also a subunit of the SEA/GATOR2 nutrient-sensing complex, where SPOP-mediated K63-ubiquitination of SEC13 attenuates GATOR2 integrity and suppresses mTORC1 signaling [PMID:21454883, PMID:38242269]. Additional partners modulate COPII assembly and trafficking, including the Sec13/Sec31A-associated factor p125A, the TRAPPIII subunit TRAPPC12, and PAQR3 [PMID:20679433, PMID:28240221, PMID:30466064].","teleology":[{"year":2006,"claim":"Established that Sec13/Sec31 is the structural building block of the COPII outer coat, answering whether the outer layer can self-organize into a vesicle-scale cage.","evidence":"Cryo-EM and single-particle analysis of purified self-assembled Sec13/31 cages","pmids":["16407955"],"confidence":"High","gaps":["30 Å resolution leaves side-chain contacts unresolved","Does not address how membrane and Sec23/24 inner coat engage the lattice in vivo"]},{"year":2003,"claim":"Showed SEC13 has a nuclear pore role distinct from secretion by demonstrating direct binding to Nup96 and nucleocytoplasmic shuttling, expanding SEC13 beyond COPII.","evidence":"Yeast two-hybrid, reciprocal Co-IP, FRAP, immuno-EM, and competition assay in human cells","pmids":["14517296"],"confidence":"High","gaps":["Did not resolve the structural basis of the Sec13–Nup96 interface","Functional consequence of shuttling not defined"]},{"year":2008,"claim":"Defined the in vivo cargo specificity of the COPII outer coat, showing SEC13/31 is dispensable for membrane curvature but required for collagen export and inner/outer-layer coupling.","evidence":"siRNA knockdown with EM, live imaging, secretion assays in primary fibroblasts, and zebrafish morpholino","pmids":["18713835"],"confidence":"High","gaps":["Molecular basis of large-cargo selectivity unresolved","How coupling is regulated not defined"]},{"year":2009,"claim":"Unified COPII and NPC scaffold architecture by solving the Nup84-Nup145C-Sec13 edge element and showing it mirrors the Sec31 ACE1 interaction.","evidence":"X-ray crystallography of the Nup84-Nup145C-Sec13 complex with Y-complex modeling","pmids":["19855394"],"confidence":"High","gaps":["Full Y-complex assembly in the NPC not captured","Does not address how SEC13 partitions between COPII and NPC pools"]},{"year":2010,"claim":"Demonstrated SEC13 also templates COPII via Sec16, establishing the ACE1 edge element as a reusable assembly principle.","evidence":"2.7 Å crystal structure of the Sec16 central domain–Sec13 complex with in vivo complementation","pmids":["20696705"],"confidence":"High","gaps":["How Sec16 and Sec31 ACE1 elements are coordinated at ER exit sites unresolved"]},{"year":2010,"claim":"Identified p125A as a stable third subunit of cytosolic Sec13/Sec31A heterohexamers, refining the resting-state composition of the outer coat.","evidence":"Reciprocal Co-IP, gel filtration, domain mapping, and siRNA functional assays","pmids":["20679433"],"confidence":"High","gaps":["Stoichiometry within budding vesicles not established","Mechanism by which p125A maintains Golgi morphology unclear"]},{"year":2011,"claim":"Placed SEC13 in the SEA complex, revealing a third scaffold role connected to nutrient signaling and trafficking.","evidence":"MS proteomics, Co-IP, structural modeling, and yeast genetics with vacuole localization","pmids":["21454883"],"confidence":"High","gaps":["SEC13's structural contribution within SEA not resolved","Direct link to downstream signaling not yet established here"]},{"year":2012,"claim":"Provided genetic evidence that COPII function (via the Sec13–Sec31a interaction) is essential for ER integrity and digestive organ development.","evidence":"Zebrafish C-terminal truncation mutant with Co-IP, EM, UPR and apoptosis readouts","pmids":["22609279"],"confidence":"High","gaps":["Cell-type basis of differential vulnerability not defined"]},{"year":2014,"claim":"Genetically separated SEC13's NPC role from its COPII role, showing the nuclear-pore function specifically drives retinal development.","evidence":"Zebrafish sec13 mutant with sec31a/b knockdown, brefeldin A controls, and nup107 epistasis","pmids":["24627485"],"confidence":"High","gaps":["How SEC13 dosage is partitioned between NPC and COPII in vivo unknown"]},{"year":2017,"claim":"Identified TRAPPIII (TRAPPC12) as a positive modulator that recognizes the assembled Sec13/Sec31A tetramer to promote outer-coat assembly.","evidence":"Co-IP binding requirement, TRAPPC12 KO/KD, ER-to-Golgi transport and localization assays","pmids":["28240221"],"confidence":"Medium","gaps":["Structural basis of tetramer-specific recognition unresolved","Single laboratory"]},{"year":2018,"claim":"Mapped how Sec31's disordered C-terminus governs the flexibility and size homogeneity of Sec13/31 cages, linking sequence to lattice mechanics.","evidence":"Cryo-EM with molecular dynamics flexible fitting on deletion mutants","pmids":["30172710"],"confidence":"Medium","gaps":["Functional consequence of altered flexibility in vivo not tested"]},{"year":2018,"claim":"Added PAQR3 as a factor that tethers COPII vesicles to the Golgi by binding the WD domains of Sec13/Sec31A.","evidence":"APEX2 proximity labeling, Co-IP domain mapping, PAQR3 KO with BFA washout and RUSH assays","pmids":["30466064"],"confidence":"Medium","gaps":["Whether PAQR3 acts directly on the coat or on tethering machinery unclear","Single laboratory"]},{"year":2022,"claim":"Connected SEC13-dependent COPII secretion to a physiological output, showing it is required for oligodendrocyte differentiation via autocrine pleiotrophin secretion.","evidence":"Conditional Sec13 KO, remyelination model, secretome analysis, and PTN rescue","pmids":["35143418"],"confidence":"Medium","gaps":["Whether SEC13's NPC/SEA roles also contribute not excluded","Single laboratory"]},{"year":2024,"claim":"Defined a regulatory mechanism for the SEA/GATOR2 role: SPOP-mediated K63-ubiquitination of SEC13 attenuates GATOR2 and suppresses mTORC1.","evidence":"Co-IP, K63-linkage ubiquitination assay, and Sec13-knockdown rescue of SPOP phenotypes","pmids":["38242269"],"confidence":"Medium","gaps":["Ubiquitination site on SEC13 not mapped","Single laboratory"]},{"year":null,"claim":"How a single SEC13 protein is partitioned among COPII, NPC, and SEA/GATOR2 scaffolds and how that partitioning is regulated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative measurement of SEC13 pool distribution across complexes","Regulatory inputs controlling complex assignment in mammalian cells unknown","Many partner interactions (presenilin-1, rabphilin-11, VISA, Pgm1/Ubqln1) lack reciprocal/structural validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,6,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4,10,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,12]}],"complexes":["COPII outer coat (Sec13/Sec31)","nuclear pore complex Y-complex","SEA/GATOR2 complex"],"partners":["SEC31A","SEC16","NUP96","NUP84","NUP145C","SEC23IP","TRAPPC12","PAQR3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55735","full_name":"Protein SEC13 homolog","aliases":["GATOR2 complex protein SEC13","SEC13-like protein 1","SEC13-related protein"],"length_aa":322,"mass_kda":35.5,"function":"Functions as a component of the nuclear pore complex (NPC) and the COPII coat (PubMed:8972206). At the endoplasmic reticulum, SEC13 is involved in the biogenesis of COPII-coated vesicles (PubMed:8972206). Required for the exit of adipsin (CFD/ADN), an adipocyte-secreted protein from the endoplasmic reticulum (By similarity) As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:25457612, PubMed:27487210, PubMed:35831510, PubMed:36528027). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:26972053, PubMed:27487210). Within the GATOR2 complex, SEC13 and SEH1L are required to stabilize the complex (PubMed:35831510)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Nucleus, nuclear pore complex; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/P55735/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC13","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000157020","cell_line_id":"CID000903","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"nuclear_membrane","grade":2}],"interactors":[{"gene":"CSNK1A1","stoichiometry":10.0},{"gene":"SEC16A","stoichiometry":10.0},{"gene":"SEC31A","stoichiometry":10.0},{"gene":"ARHGAP18","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"HNRNPA2B1","stoichiometry":0.2},{"gene":"PDCD6","stoichiometry":0.2},{"gene":"SEC24B","stoichiometry":0.2},{"gene":"NUP85","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000903","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"617418","title":"WD REPEAT-CONTAINING PROTEIN 59; WDR59","url":"https://www.omim.org/entry/617418"},{"mim_id":"615359","title":"MEIOSIS REGULATOR FOR OOCYTE DEVELOPMENT; MIOS","url":"https://www.omim.org/entry/615359"},{"mim_id":"614191","title":"DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5","url":"https://www.omim.org/entry/614191"},{"mim_id":"612854","title":"SEC16 HOMOLOG A, ENDOPLASMIC RETICULUM EXPORT FACTOR; SEC16A","url":"https://www.omim.org/entry/612854"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC13"},"hgnc":{"alias_symbol":["SEC13R","npp-20"],"prev_symbol":["D3S1231E","SEC13L1"]},"alphafold":{"accession":"P55735","domains":[{"cath_id":"2.130.10.10","chopping":"155-165_177-307","consensus_level":"medium","plddt":91.9818,"start":155,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55735","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55735-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55735-F1-predicted_aligned_error_v6.png","plddt_mean":89.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC13","jax_strain_url":"https://www.jax.org/strain/search?query=SEC13"},"sequence":{"accession":"P55735","fasta_url":"https://rest.uniprot.org/uniprotkb/P55735.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55735/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55735"}},"corpus_meta":[{"pmid":"16407955","id":"PMC_16407955","title":"Structure of the Sec13/31 COPII coat cage.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16407955","citation_count":257,"is_preprint":false},{"pmid":"18713835","id":"PMC_18713835","title":"Efficient coupling of Sec23-Sec24 to Sec13-Sec31 drives COPII-dependent collagen secretion and is essential for normal craniofacial development.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18713835","citation_count":153,"is_preprint":false},{"pmid":"20675572","id":"PMC_20675572","title":"NENA, a Lotus japonicus homolog of Sec13, is required for rhizodermal infection by arbuscular mycorrhiza fungi and rhizobia but dispensable for cortical endosymbiotic development.","date":"2010","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/20675572","citation_count":152,"is_preprint":false},{"pmid":"21454883","id":"PMC_21454883","title":"A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae.","date":"2011","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/21454883","citation_count":119,"is_preprint":false},{"pmid":"9409822","id":"PMC_9409822","title":"Control of amino acid permease sorting in the late secretory pathway of Saccharomyces cerevisiae by SEC13, LST4, LST7 and LST8.","date":"1997","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9409822","citation_count":119,"is_preprint":false},{"pmid":"20696705","id":"PMC_20696705","title":"Structure of the Sec13-Sec16 edge element, a template for assembly of the COPII vesicle coat.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20696705","citation_count":84,"is_preprint":false},{"pmid":"14517296","id":"PMC_14517296","title":"Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the nuclear pore complex.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14517296","citation_count":75,"is_preprint":false},{"pmid":"19855394","id":"PMC_19855394","title":"Molecular architecture of the Nup84-Nup145C-Sec13 edge element in the nuclear pore complex lattice.","date":"2009","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19855394","citation_count":65,"is_preprint":false},{"pmid":"9535892","id":"PMC_9535892","title":"Folding a WD repeat propeller. Role of highly conserved aspartic acid residues in the G protein beta subunit and Sec13.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9535892","citation_count":63,"is_preprint":false},{"pmid":"20679433","id":"PMC_20679433","title":"p125A exists as part of the mammalian Sec13/Sec31 COPII subcomplex to facilitate ER-Golgi transport.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20679433","citation_count":49,"is_preprint":false},{"pmid":"24627485","id":"PMC_24627485","title":"The nuclear pore complex function of Sec13 protein is required for cell survival during retinal development.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24627485","citation_count":41,"is_preprint":false},{"pmid":"8952469","id":"PMC_8952469","title":"Analysis of the physical properties and molecular modeling of Sec13: A WD repeat protein involved in vesicular traffic.","date":"1996","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8952469","citation_count":34,"is_preprint":false},{"pmid":"22609279","id":"PMC_22609279","title":"Sec13 safeguards the integrity of the endoplasmic reticulum and organogenesis of the digestive system in zebrafish.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22609279","citation_count":31,"is_preprint":false},{"pmid":"35143418","id":"PMC_35143418","title":"Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35143418","citation_count":27,"is_preprint":false},{"pmid":"7987303","id":"PMC_7987303","title":"Molecular characterization of a novel human gene, SEC13R, related to the yeast secretory pathway gene SEC13, and mapping to a conserved linkage group on human chromosome 3p24-p25 and mouse chromosome 6.","date":"1994","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7987303","citation_count":27,"is_preprint":false},{"pmid":"28240221","id":"PMC_28240221","title":"Mammalian TRAPPIII Complex positively modulates the recruitment of Sec13/31 onto COPII vesicles.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28240221","citation_count":26,"is_preprint":false},{"pmid":"21984910","id":"PMC_21984910","title":"Association of calcineurin with the COPI protein Sec28 and the COPII protein Sec13 revealed by quantitative proteomics.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21984910","citation_count":23,"is_preprint":false},{"pmid":"26631972","id":"PMC_26631972","title":"Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26631972","citation_count":22,"is_preprint":false},{"pmid":"10747849","id":"PMC_10747849","title":"Physical and functional interaction of rabphilin-11 with mammalian Sec13 protein. Implication in vesicle trafficking.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10747849","citation_count":21,"is_preprint":false},{"pmid":"23519012","id":"PMC_23519012","title":"Early stages of retinal development depend on Sec13 function.","date":"2013","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/23519012","citation_count":20,"is_preprint":false},{"pmid":"22331354","id":"PMC_22331354","title":"Epithelial organization and cyst lumen expansion require efficient Sec13-Sec31-driven secretion.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22331354","citation_count":18,"is_preprint":false},{"pmid":"30466064","id":"PMC_30466064","title":"PAQR3 Regulates Endoplasmic Reticulum-to-Golgi Trafficking of COPII Vesicle via Interaction with Sec13/Sec31 Coat Proteins.","date":"2018","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/30466064","citation_count":18,"is_preprint":false},{"pmid":"11821054","id":"PMC_11821054","title":"A DMSO-sensitive conditional mutant of the fission yeast orthologue of the Saccharomyces cerevisiae SEC13 gene is defective in septation.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11821054","citation_count":14,"is_preprint":false},{"pmid":"37311539","id":"PMC_37311539","title":"Functional differentiation of Sec13 paralogues in the euglenozoan protists.","date":"2023","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/37311539","citation_count":12,"is_preprint":false},{"pmid":"29948782","id":"PMC_29948782","title":"Sec13 is a positive regulator of VISA-mediated antiviral signaling.","date":"2018","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/29948782","citation_count":12,"is_preprint":false},{"pmid":"30172710","id":"PMC_30172710","title":"Flexibility of the Sec13/31 cage is influenced by the Sec31 C-terminal disordered domain.","date":"2018","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/30172710","citation_count":10,"is_preprint":false},{"pmid":"16000881","id":"PMC_16000881","title":"Sec13 induces genomic instability in U2OS cells.","date":"2005","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16000881","citation_count":9,"is_preprint":false},{"pmid":"36301095","id":"PMC_36301095","title":"Sar1 Interacts with Sec23/Sec24 and Sec13/Sec31 Complexes: Insight into Its Involvement in the Assembly of Coat Protein Complex II in the Microsporidian Nosema bombycis.","date":"2022","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/36301095","citation_count":8,"is_preprint":false},{"pmid":"35449150","id":"PMC_35449150","title":"Gene profiling of SEC13, SMAD7, GHRL, long non-coding RNA GHRLOS, HIF-1α in gastric cancer patients.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35449150","citation_count":7,"is_preprint":false},{"pmid":"38242269","id":"PMC_38242269","title":"SPOP negatively regulates mTORC1 activity by ubiquitinating Sec13.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38242269","citation_count":6,"is_preprint":false},{"pmid":"16413257","id":"PMC_16413257","title":"Recombinant production in baculovirus-infected insect cells and purification of the mammalian Sec13/Sec31 complex.","date":"2005","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/16413257","citation_count":6,"is_preprint":false},{"pmid":"19682973","id":"PMC_19682973","title":"The coat protein complex II, COPII, protein Sec13 directly interacts with presenilin-1.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19682973","citation_count":4,"is_preprint":false},{"pmid":"28122936","id":"PMC_28122936","title":"Nucleoporins NPP-10, NPP-13 and NPP-20 are required for HCP-4 nuclear import to establish correct centromere assembly.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28122936","citation_count":4,"is_preprint":false},{"pmid":"38698045","id":"PMC_38698045","title":"COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38698045","citation_count":2,"is_preprint":false},{"pmid":"38038453","id":"PMC_38038453","title":"The ER-Golgi transport of influenza virus through NS1-Sec13 association during virus replication.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/38038453","citation_count":2,"is_preprint":false},{"pmid":"39159700","id":"PMC_39159700","title":"Sec13 promotes glycolysis by inhibiting Ubqln1 mediated Pgm1 ubiquitination in ALI.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39159700","citation_count":1,"is_preprint":false},{"pmid":"39704187","id":"PMC_39704187","title":"Long Noncoding RNA LINC02453 Inhibits HIV-1 Replication by Binding With SEC13 to Regulate the Viral Productive Cycle.","date":"2024","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/39704187","citation_count":1,"is_preprint":false},{"pmid":"36685890","id":"PMC_36685890","title":"Genetic marker identification of SEC13 gene for milk production traits in Chinese holstein.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36685890","citation_count":0,"is_preprint":false},{"pmid":"40972809","id":"PMC_40972809","title":"COPII component Sec13 is required for peripheral myelination and Schwann cell maintenance.","date":"2025","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/40972809","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.03.626618","title":"Multifunctional Roles of Sec13 Paralogues in the Euglenozoan  <i>Trypanosoma brucei</i>","date":"2024-12-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.03.626618","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.07.652703","title":"p125A (Sec23ip) couples COPII coat assembly with donor-acceptor membrane organization to facilitate tunnel-based traffic","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.07.652703","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20299,"output_tokens":6120,"usd":0.076348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14800,"output_tokens":4290,"usd":0.090625,"stage2_stop_reason":"end_turn"},"total_usd":0.166973,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Sec13 and Sec31 form a 2:2 heterotetramer that self-assembles into cuboctahedral cage structures in the absence of Sec23/24, revealing that Sec13/31 has a primary structural role in COPII coat formation. Cryo-EM reconstruction at 30 Å resolution showed a novel cuboctahedron geometry capable of forming a flexible lattice.\",\n      \"method\": \"Cryo-electron microscopy and single particle analysis of purified Sec13/31 cages\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural reconstruction with in vitro reconstitution of self-assembled cages, foundational structural result independently confirmed by subsequent studies\",\n      \"pmids\": [\"16407955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The COPII accessory protein Sec16 contains an ACE1 (ancestral coatomer element 1) domain and forms a 2:2 tetramer edge element with Sec13, analogous to the Sec13-Sec31 edge element. Crystal structure at 2.7 Å resolution showed domain swapping at the ACE1-ACE1 interface; in vivo data indicated the ACE1 of Sec31 can functionally replace the ACE1 of Sec16, supporting Sec16 as a scaffold/template for COPII coat assembly.\",\n      \"method\": \"X-ray crystallography (2.7 Å crystal structure of Sec16 central domain–Sec13 complex), in vivo complementation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with in vivo functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20696705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sec13 participates in the nuclear pore complex (NPC) Y-complex as a structural component forming a heterotrimeric edge element with Nup84 and Nup145C. Crystal structure of the 134-kDa Nup84-Nup145C-Sec13 complex showed that the heterotypic ACE1 interaction of Nup84 and Nup145C is analogous to the homotypic ACE1 interaction of Sec31 in COPII, supporting a common lattice architecture between COPII and NPC scaffolds.\",\n      \"method\": \"X-ray crystallography of Nup84-Nup145C-Sec13 complex\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with molecular modeling of Y complex, orthologous confirmation of shared ACE1 architecture\",\n      \"pmids\": [\"19855394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Sec13 directly interacts with Nup96 at the nuclear pore complex via the WD repeat region of Sec13 and the N-terminal region of Nup96. Sec13 shuttles between intranuclear sites and cytoplasm (shown by FRAP), a fraction is stably associated with NPCs during interphase, and Sec13 contains a nuclear localization signal enabling active nuclear import.\",\n      \"method\": \"Yeast two-hybrid, biochemical co-immunoprecipitation, immunofluorescence/confocal/immunoelectron microscopy, photobleaching (FRAP), cotransfection competition assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, FRAP, multiple imaging modalities, functional in vivo competition experiment confirming interaction\",\n      \"pmids\": [\"14517296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sec13 depletion causes concomitant loss of Sec31 and juxtanuclear clustering of Sec23/24-containing pre-budding complexes. Sec13/31 is not required for generation of membrane curvature at the ER (curved coated profiles persist), but efficient coupling of the inner (Sec23/24) and outer (Sec13/31) COPII layers is specifically required for collagen export from the ER in primary fibroblasts, while general secretory cargo (tsO45-G-YFP) export is unaffected.\",\n      \"method\": \"siRNA knockdown, electron microscopy, live-cell fluorescence imaging, secretion assays in primary fibroblasts, zebrafish morpholino knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, live imaging, functional secretion assays) in cell and in vivo models, result replicated across systems\",\n      \"pmids\": [\"18713835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The nuclear pore function of Sec13 (distinct from its COPII function) is specifically required for retinal development. Loss of COPII function (sec31a/b knockdown or brefeldin A) did not cause retinal lamination defects, while sec13 mutation caused NPC failure, nuclear mRNA accumulation, and p53-dependent apoptosis in retinal cells. The retinal phenotype was phenocopied by loss of NPC-specific component Nup107.\",\n      \"method\": \"Zebrafish genetic model (sec13 sq198 mutant), morpholino knockdown of sec31a/sec31b, brefeldin A treatment, nuclear mRNA localization assay, apoptosis assay, genetic epistasis with nup107 knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple controls distinguishing COPII vs. NPC function, phenocopy by NPC-specific component, multiple orthogonal experiments in one study\",\n      \"pmids\": [\"24627485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, a C-terminal truncation of Sec13 that loses affinity for Sec31a leads to ER structural disintegration in differentiated cells (chondrocytes, intestinal epithelial cells, hepatocytes), triggering unfolded protein response, cell-cycle arrest, and apoptosis, arresting digestive organ growth. This provides direct genetic evidence that COPII function is essential for digestive system organogenesis.\",\n      \"method\": \"Zebrafish genetic mutant analysis, co-immunoprecipitation (Sec13 truncation vs. Sec31a), electron microscopy of ER structure, UPR assays, apoptosis assays\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with biochemical validation of loss of Sec31a interaction, EM confirmation of ER structure, multiple cellular phenotype readouts\",\n      \"pmids\": [\"22609279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p125A forms a stable ternary complex with Sec13/Sec31A in the cytosol, existing primarily as preassembled Sec13/Sec31A/p125A heterohexamers. p125A binds the C-terminal region of Sec31A (residues 260–600 of p125A) via a domain distinct from its Sec23A-binding domain. Loss of p125A disrupts Golgi morphology and ER protein export.\",\n      \"method\": \"Co-immunoprecipitation, gel filtration, immunodepletion, siRNA knockdown with ER export and Golgi morphology assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, gel filtration, domain mapping, and functional rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"20679433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sec13 is a component of the SEA (Seh1-Associated) complex in yeast, which also contains Seh1, Npr2, Npr3, and Sea1–Sea4 proteins. SEA complex proteins share structural characteristics with COPI, COPII, NPC, and vesicle tethering complexes HOPS/CORVET. The SEA complex dynamically associates with the vacuole in vivo and has roles in intracellular trafficking, amino acid biogenesis, and nitrogen starvation response.\",\n      \"method\": \"Mass spectrometry proteomics, co-immunoprecipitation, computational structural modeling, yeast genetics/genetic assays, in vivo vacuole localization\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS proteomics, biochemical Co-IP, in vivo localization, and genetic assays all converging on SEA complex composition and function\",\n      \"pmids\": [\"21454883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The conserved aspartic acid residues in WD repeat blades of Sec13 (yeast) are important but not individually essential for folding of the WD propeller structure. Mutating conserved Asp to Gly in individual blades of Sec13 affects folding in vitro and in COS-7 cells equally; double mutants fold poorly. The repeats most affecting folding differ between Sec13 and Gβ, indicating different folding pathways for different WD repeat proteins.\",\n      \"method\": \"Site-directed mutagenesis of conserved Asp residues, in vitro folding assay, expression in COS-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with in vitro and in vivo folding assays, single laboratory study\",\n      \"pmids\": [\"9535892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRAPPIII complex (via its specific subunit TRAPPC12) binds to the Sec13/Sec31A tetramer (but not to Sec13 or Sec31A alone) and positively modulates the assembly of the COPII outer layer during vesicle formation at ER exit sites. TRAPPC12 localizes to ER exit sites/ERGIC, and its deletion disperses the ERGIC and delays ER-to-Golgi transport.\",\n      \"method\": \"Co-immunoprecipitation, TRAPPC12 knockout/knockdown, ER-to-Golgi transport assay, immunofluorescence localization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining binding requirement for tetramer, functional KO data, localization studies; single laboratory\",\n      \"pmids\": [\"28240221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAQR3 interacts with the WD domains of Sec13 and Sec31A (via its N-terminal end) and facilitates tethering of COPII vesicles to the Golgi. PAQR3 deletion delays ER-to-Golgi trafficking (assessed by BFA washout and RUSH assay). PAQR3 enhances Golgi localization of Sec13 and Sec31A.\",\n      \"method\": \"APEX2 proximity labeling, Co-immunoprecipitation, PAQR3 knockout, BFA washout assay, RUSH assay, domain mapping\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling, Co-IP domain mapping, KO with trafficking functional assay; single laboratory\",\n      \"pmids\": [\"30466064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPOP mediates K63-linked ubiquitination of Sec13, a component of the GATOR2 complex. K63-ubiquitination of Sec13 attenuates its interaction with other GATOR2 components, thereby suppressing GATOR2 activity and negatively regulating mTORC1 signaling in response to amino acids. SPOP deficiency promotes cancer cell proliferation/migration in a Sec13-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63 linkage), Sec13 knockdown rescue experiment, mTORC1 activity assay, cell proliferation/migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination biochemistry, and genetic epistasis (SPOP KD rescued by Sec13 KD); single laboratory\",\n      \"pmids\": [\"38242269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sec13-dependent COPII protein trafficking is required for oligodendrocyte (OL) differentiation and myelination. Ablation of Sec13 in OL lineage prevents OPC differentiation and inhibits myelination/remyelination. Loss of Sec13 alters the OL secretome and specifically inhibits secretion of pleiotrophin (PTN), which acts as an autocrine factor promoting OL differentiation and myelin repair.\",\n      \"method\": \"Conditional Sec13 knockout in OL lineage, remyelination model, secretome analysis, PTN rescue experiments, COPII enhancer (TUDCA) treatment, ectopic COPII component expression\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype, secretome analysis identifying PTN, autocrine rescue experiment; single laboratory\",\n      \"pmids\": [\"35143418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian Sec13 (mSec13p) directly binds rabphilin-11 in cell-free and intact cell systems. The interaction is enhanced by GTP-Rab11p. Disruption of the rabphilin-11–mSec13p interaction by overexpression of the mSec13p-binding domain of rabphilin-11 impairs vesicle trafficking in the perinuclear/Golgi region.\",\n      \"method\": \"Cell-free binding assay, co-immunoprecipitation from intact cells, immunofluorescence colocalization, dominant-negative overexpression of binding domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-free binding and Co-IP from cells, dominant-negative functional evidence; single laboratory\",\n      \"pmids\": [\"10747849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sec13 directly interacts with presenilin-1 (PS1); the interaction maps to the N-terminal part of the large hydrophilic PS1 cytoplasmic loop and the first WD40-repeat of Sec13.\",\n      \"method\": \"Pulldown/binding assay, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single interaction mapping study, limited functional follow-up described in abstract, single laboratory\",\n      \"pmids\": [\"19682973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sec13 functions as a positive regulator of VISA (MAVS)-mediated antiviral signaling. Sec13 specifically co-immunoprecipitates with VISA. Overexpression of Sec13 increases VISA aggregation and ubiquitination, enhances IRF3 phosphorylation and dimerization, and promotes IFN-β production. Knockdown of Sec13 attenuates Sendai virus-induced IRF3 activation and IFN-β production.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown, IRF3 phosphorylation/dimerization assays, IFN-β reporter/ELISA\",\n      \"journal\": \"Virus genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, gain- and loss-of-function with molecular pathway readouts; single laboratory\",\n      \"pmids\": [\"29948782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sec13 forms a protein complex with Pgm1 (phosphoglucomutase 1) and Ubqln1. Sec13 inhibits Ubqln1-mediated K48-linked ubiquitination and degradation of Pgm1, thereby stabilizing Pgm1 and promoting glycolysis (G6P and lactate production) in acute lung injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Sec13/Pgm1/Ubqln1 knockdown/overexpression, metabolite measurement (G6P, lactate)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay with functional metabolic readouts, but single laboratory, limited mechanistic validation\",\n      \"pmids\": [\"39159700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal disordered region of Sec31 (residues 820–1220) regulates the flexibility and rigidity of Sec13/31 cages. Deletion of this region produces Sec13/31ΔC cages with more homogeneous size distribution but greater conformational heterogeneity within cuboctahedra. Cryo-EM and MD flexible fitting identified a new hinge for Sec31 β-propeller domain flexing and increased flexibility of a known hinge.\",\n      \"method\": \"Cryo-EM, biophysical characterization of purified complexes, molecular dynamics flexible fitting (MDFF)\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural analysis with MD simulations, deletion mutant analysis; single laboratory\",\n      \"pmids\": [\"30172710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human Sec13 localizes to kinetochores at metaphase during mitosis. Overexpression of Sec13 causes cells to evade mitotic arrest in response to spindle damage (nocodazole), leading to G1-like phase and apoptotic cell death, and results in giant nuclei formation, suggesting a role in the metaphase/anaphase transition.\",\n      \"method\": \"GFP-tagging and live cell imaging, cell cycle analysis, nocodazole treatment, apoptosis assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single laboratory, GFP localization and overexpression with phenotypic readouts but no mechanistic pathway placement\",\n      \"pmids\": [\"16000881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Calcineurin A (Cna1) physically associates with the COPII component Sec13 in Cryptococcus neoformans, as identified by quantitative mass spectrometry and confirmed by co-immunoprecipitation. Cna1 co-localizes with Sec13 at ER-associated puncta during high-temperature stress.\",\n      \"method\": \"Mass spectrometry from immunoprecipitation, co-immunoprecipitation, immunofluorescence colocalization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP confirmation of MS hit, localization data, but no functional follow-up on the interaction mechanism; single laboratory, non-mammalian organism\",\n      \"pmids\": [\"21984910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In euglenozoan protists (diplonemids), two Sec13 paralogues have functionally diverged: Sec13a interacts with COPII components and the NPC, while Sec13b interacts with Sec16 and SEA/GATOR complex components. This demonstrates that the three established Sec13 roles (COPII, NPC, SEA/GATOR) can be distributed across paralogues.\",\n      \"method\": \"Co-immunoprecipitation/protein interaction studies, subcellular localization imaging, yeast two-hybrid\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction and localization data in a non-mammalian organism (diplonemid protist), single laboratory\",\n      \"pmids\": [\"37311539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, the Sec13 orthologue NPP-20 (a nucleoporin) is required for nuclear import of the centromeric protein HCP-4. Knockdown of NPP-20 causes HCP-4 to remain in the cytosol during prophase, preventing its incorporation into centromeres and causing chromosomal segregation defects.\",\n      \"method\": \"RNAi knockdown in C. elegans, immunofluorescence localization of HCP-4, chromosome segregation phenotype analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNAi knockdown with localization and phenotypic readouts in C. elegans; NPP-20 is the SEC13 orthologue (alias confirmed) but functional follow-up is limited to localization\",\n      \"pmids\": [\"28122936\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC13 is a WD40-repeat β-propeller protein that serves as a structural component in at least three distinct multi-protein complexes: (1) the COPII outer coat, where Sec13/Sec31 heterotetramers self-assemble into cuboctahedral cage lattices to drive ER-to-Golgi vesicle formation (with a specific requirement for large cargo such as collagen), (2) the nuclear pore complex Y-complex scaffold, where Sec13 forms an ACE1-based edge element with Nup84/Nup145C and stably interacts with Nup96 while also shuttling between nucleus and cytoplasm, and (3) the SEA/GATOR2 nutrient-sensing complex, where SPOP-mediated K63-ubiquitination of Sec13 attenuates GATOR2 integrity and suppresses mTORC1 signaling; additionally, Sec13 interacts with the COPII scaffold protein Sec16 via a second ACE1 edge element, is positively modulated in COPII outer-layer assembly by the TRAPPIII complex, and participates in VISA-mediated antiviral IFN-β signaling and autocrine pleiotrophin secretion required for oligodendrocyte myelination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC13 is a WD40-repeat β-propeller protein that functions as a shared structural module across multiple multi-protein scaffolds, most prominently the COPII vesicle coat that drives ER-to-Golgi transport [#0, #4]. With Sec31 it forms a 2:2 heterotetramer that self-assembles into cuboctahedral cage lattices independently of the inner Sec23/24 layer, defining its primary role as an outer-coat structural element [#0]; the C-terminal disordered region of Sec31 tunes the rigidity and conformational heterogeneity of these cages [#18]. SEC13 contributes a recurring ACE1-based edge element: it pairs with the COPII scaffold Sec16 through domain-swapped ACE1–ACE1 interfaces [#1], and an equivalent architecture builds the nuclear pore Y-complex, where SEC13 forms a heterotrimeric edge with Nup84 and Nup145C and stably binds Nup96, linking COPII and NPC scaffolds to a common lattice design [#2, #3]. These two activities are functionally separable: COPII-dependent SEC13 function is specifically required for export of large cargo such as collagen and for ER/digestive-organ and oligodendrocyte secretory biology [#4, #6, #13], whereas its nuclear-pore function supports nucleocytoplasmic transport and is selectively required for retinal development [#5]. SEC13 is also a subunit of the SEA/GATOR2 nutrient-sensing complex, where SPOP-mediated K63-ubiquitination of SEC13 attenuates GATOR2 integrity and suppresses mTORC1 signaling [#8, #12]. Additional partners modulate COPII assembly and trafficking, including the Sec13/Sec31A-associated factor p125A, the TRAPPIII subunit TRAPPC12, and PAQR3 [#7, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that Sec13/Sec31 is the structural building block of the COPII outer coat, answering whether the outer layer can self-organize into a vesicle-scale cage.\",\n      \"evidence\": \"Cryo-EM and single-particle analysis of purified self-assembled Sec13/31 cages\",\n      \"pmids\": [\"16407955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"30 Å resolution leaves side-chain contacts unresolved\", \"Does not address how membrane and Sec23/24 inner coat engage the lattice in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed SEC13 has a nuclear pore role distinct from secretion by demonstrating direct binding to Nup96 and nucleocytoplasmic shuttling, expanding SEC13 beyond COPII.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, FRAP, immuno-EM, and competition assay in human cells\",\n      \"pmids\": [\"14517296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the Sec13–Nup96 interface\", \"Functional consequence of shuttling not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the in vivo cargo specificity of the COPII outer coat, showing SEC13/31 is dispensable for membrane curvature but required for collagen export and inner/outer-layer coupling.\",\n      \"evidence\": \"siRNA knockdown with EM, live imaging, secretion assays in primary fibroblasts, and zebrafish morpholino\",\n      \"pmids\": [\"18713835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of large-cargo selectivity unresolved\", \"How coupling is regulated not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Unified COPII and NPC scaffold architecture by solving the Nup84-Nup145C-Sec13 edge element and showing it mirrors the Sec31 ACE1 interaction.\",\n      \"evidence\": \"X-ray crystallography of the Nup84-Nup145C-Sec13 complex with Y-complex modeling\",\n      \"pmids\": [\"19855394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full Y-complex assembly in the NPC not captured\", \"Does not address how SEC13 partitions between COPII and NPC pools\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated SEC13 also templates COPII via Sec16, establishing the ACE1 edge element as a reusable assembly principle.\",\n      \"evidence\": \"2.7 Å crystal structure of the Sec16 central domain–Sec13 complex with in vivo complementation\",\n      \"pmids\": [\"20696705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Sec16 and Sec31 ACE1 elements are coordinated at ER exit sites unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified p125A as a stable third subunit of cytosolic Sec13/Sec31A heterohexamers, refining the resting-state composition of the outer coat.\",\n      \"evidence\": \"Reciprocal Co-IP, gel filtration, domain mapping, and siRNA functional assays\",\n      \"pmids\": [\"20679433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry within budding vesicles not established\", \"Mechanism by which p125A maintains Golgi morphology unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed SEC13 in the SEA complex, revealing a third scaffold role connected to nutrient signaling and trafficking.\",\n      \"evidence\": \"MS proteomics, Co-IP, structural modeling, and yeast genetics with vacuole localization\",\n      \"pmids\": [\"21454883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SEC13's structural contribution within SEA not resolved\", \"Direct link to downstream signaling not yet established here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided genetic evidence that COPII function (via the Sec13–Sec31a interaction) is essential for ER integrity and digestive organ development.\",\n      \"evidence\": \"Zebrafish C-terminal truncation mutant with Co-IP, EM, UPR and apoptosis readouts\",\n      \"pmids\": [\"22609279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type basis of differential vulnerability not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetically separated SEC13's NPC role from its COPII role, showing the nuclear-pore function specifically drives retinal development.\",\n      \"evidence\": \"Zebrafish sec13 mutant with sec31a/b knockdown, brefeldin A controls, and nup107 epistasis\",\n      \"pmids\": [\"24627485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SEC13 dosage is partitioned between NPC and COPII in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified TRAPPIII (TRAPPC12) as a positive modulator that recognizes the assembled Sec13/Sec31A tetramer to promote outer-coat assembly.\",\n      \"evidence\": \"Co-IP binding requirement, TRAPPC12 KO/KD, ER-to-Golgi transport and localization assays\",\n      \"pmids\": [\"28240221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of tetramer-specific recognition unresolved\", \"Single laboratory\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped how Sec31's disordered C-terminus governs the flexibility and size homogeneity of Sec13/31 cages, linking sequence to lattice mechanics.\",\n      \"evidence\": \"Cryo-EM with molecular dynamics flexible fitting on deletion mutants\",\n      \"pmids\": [\"30172710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of altered flexibility in vivo not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added PAQR3 as a factor that tethers COPII vesicles to the Golgi by binding the WD domains of Sec13/Sec31A.\",\n      \"evidence\": \"APEX2 proximity labeling, Co-IP domain mapping, PAQR3 KO with BFA washout and RUSH assays\",\n      \"pmids\": [\"30466064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PAQR3 acts directly on the coat or on tethering machinery unclear\", \"Single laboratory\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SEC13-dependent COPII secretion to a physiological output, showing it is required for oligodendrocyte differentiation via autocrine pleiotrophin secretion.\",\n      \"evidence\": \"Conditional Sec13 KO, remyelination model, secretome analysis, and PTN rescue\",\n      \"pmids\": [\"35143418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SEC13's NPC/SEA roles also contribute not excluded\", \"Single laboratory\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a regulatory mechanism for the SEA/GATOR2 role: SPOP-mediated K63-ubiquitination of SEC13 attenuates GATOR2 and suppresses mTORC1.\",\n      \"evidence\": \"Co-IP, K63-linkage ubiquitination assay, and Sec13-knockdown rescue of SPOP phenotypes\",\n      \"pmids\": [\"38242269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on SEC13 not mapped\", \"Single laboratory\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single SEC13 protein is partitioned among COPII, NPC, and SEA/GATOR2 scaffolds and how that partitioning is regulated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative measurement of SEC13 pool distribution across complexes\", \"Regulatory inputs controlling complex assignment in mammalian cells unknown\", \"Many partner interactions (presenilin-1, rabphilin-11, VISA, Pgm1/Ubqln1) lack reciprocal/structural validation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 6, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4, 10, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"complexes\": [\n      \"COPII outer coat (Sec13/Sec31)\",\n      \"nuclear pore complex Y-complex\",\n      \"SEA/GATOR2 complex\"\n    ],\n    \"partners\": [\n      \"SEC31A\",\n      \"SEC16\",\n      \"NUP96\",\n      \"NUP84\",\n      \"NUP145C\",\n      \"SEC23IP\",\n      \"TRAPPC12\",\n      \"PAQR3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}