{"gene":"S100A13","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1998,"finding":"S100A13 was identified as a component of a brain-derived multiprotein complex containing FGF-1 and p40 synaptotagmin-1 (Syn-1), and amlexanox (which binds S100A13) repressed heat shock-induced release of FGF-1 and p40 Syn-1 in a concentration-dependent manner, implicating S100A13 in regulation of the FGF-1 non-classical release pathway.","method":"Purification of brain-derived complex, co-purification/association assay, pharmacological inhibition with amlexanox in cell-based stress release assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-purification from tissue plus functional cell-based pharmacological inhibition, single lab, two orthogonal methods","pmids":["9712836"],"is_preprint":false},{"year":2001,"finding":"S100A13 participates directly in heat shock-induced FGF-1 release: co-expression of S100A13 with FGF-1 represses constitutive S100A13 release and enables stress-induced co-release; a deletion mutant of S100A13 lacking its basic residue-rich C-terminal domain acts as a dominant-negative inhibitor of FGF-1 release; S100A13 expression also enables release of a normally non-releasable Cys-free FGF-1 mutant.","method":"Overexpression and dominant-negative deletion mutant studies in NIH 3T3 cells, conditioned medium analysis, ammonium sulfate solubility assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods (WT overexpression, dominant-negative mutant, Cys-free FGF-1 rescue), replicated functional readout","pmids":["11410600"],"is_preprint":false},{"year":2003,"finding":"S100A13 mediates the copper-dependent, stress-induced non-classical release of IL-1α: IL-1α associates intracellularly with S100A13 in a Cu2+-dependent manner; a dominant-negative S100A13 mutant (lacking its novel sequence) represses IL-1α export; wild-type S100A13 overexpression eliminates the requirement for stress-induced transcription for IL-1α release.","method":"Co-immunoprecipitation, dominant-negative S100A13 mutant expression, conditioned medium western blot in U937 and NIH 3T3 cells, Cu2+ chelation experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction, dominant-negative genetic approach, copper chelation pharmacology, two cell lines, multiple orthogonal methods","pmids":["12746488"],"is_preprint":false},{"year":1999,"finding":"S100A13 (and S100A12) directly bind the anti-allergic drugs amlexanox, cromolyn, and tranilast, as demonstrated by affinity chromatography; this binding is calcium-sensitive and distinct from calmodulin interactions.","method":"Drug-coupled affinity chromatography, reversed-phase HPLC, cDNA sequencing of isolated proteins, binding confirmed with recombinant protein","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity chromatography with recombinant protein validation, single lab, two orthogonal methods","pmids":["10051426"],"is_preprint":false},{"year":2000,"finding":"Human recombinant S100A13 is a homodimer that binds four Ca2+ per dimer in two sets of sites with positive cooperativity (high- and low-affinity); Ca2+ binding causes conformational changes detectable by fluorescence and CD; S100A13 uniquely does not expose hydrophobic patches upon Ca2+ binding (unlike most S100 proteins); in human smooth muscle cells, S100A13 localizes to the perinuclear area, distinct from S100A2 (nuclear) and S100A1 (stress fibers).","method":"Flow dialysis, fluorescence spectrophotometry, circular dichroism, immunofluorescence with specific antisera in multiple cell types","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical characterization with multiple orthogonal biophysical methods plus cell localization; rigorous single-study approach","pmids":["10722710"],"is_preprint":false},{"year":2002,"finding":"S100A13 undergoes Ca2+-dependent translocation in endothelial cells via the classical Golgi-ER pathway in response to angiotensin II stimulation, a pathway distinct from S100A6 (which uses actin stress fibers).","method":"Live cell imaging/translocation assays in endothelial cells, pharmacological disruption of Golgi-ER and actin pathways","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization experiment with functional pathway discrimination, single lab, pharmacological and imaging methods","pmids":["12118070"],"is_preprint":false},{"year":2006,"finding":"S100A13 binds Cu2+ and Ca2+ independently with similar micromolar affinity (two atoms per subunit); Ca2+ stabilizes S100A13 while Cu2+ destabilizes it; S100A13 can bind both ions simultaneously; Cu2+ binding is important for FGF-1 homodimer formation and subsequent non-classical secretion.","method":"Isothermal titration calorimetry, multidimensional NMR spectroscopy, terbium binding, thermal denaturation by far-UV CD, limited trypsin digestion, hydrogen-deuterium exchange","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods including NMR and ITC, rigorous single-study approach","pmids":["16766622"],"is_preprint":false},{"year":2006,"finding":"FGF-1 and S100A13 are co-released from astrocytes upon serum-deprivation stress via a non-vesicular (Brefeldin A-insensitive) pathway; S100A13 is the major protein co-immunoprecipitated with FGF-1; the interaction requires the C-terminal 11 amino acid peptide of S100A13 and is Ca2+-sensitive; a Δ88–98 S100A13 mutant selectively blocks FGF-1 release but not S100A13 release itself; amlexanox blocks both; Ca2+ chelation (BAPTA-AM) abolishes both releases.","method":"Immunocytochemistry, immunoblot of conditioned medium, immunoprecipitation, GST/Strep-tag pull-down with deletion mutants, pharmacological inhibition (amlexanox, BAPTA-AM, Brefeldin A), Ca2+ imaging","journal":"Neurochemistry international","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown, deletion mutant dominant-negative, Ca2+ imaging, pharmacological validation, multiple orthogonal methods in single study","pmids":["16519964"],"is_preprint":false},{"year":2007,"finding":"ApoS100A13 (calcium-free form) preferentially binds phosphatidylserine lipid vesicles; Ca2+-bound S100A13 binds weakly; apoS100A13 undergoes subtle conformational change exposing hydrophobic surfaces upon lipid binding; these lipid interactions are proposed to facilitate membrane translocation during non-classical FGF-1 secretion.","method":"Isothermal titration calorimetry, steady-state fluorescence, equilibrium thermal unfolding, ANS binding, limited trypsin digestion, far-UV CD with phosphatidylserine SUVs","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biophysical in vitro methods, single lab, functional interpretation inferred but not directly demonstrated","pmids":["17991455"],"is_preprint":false},{"year":2007,"finding":"Ca2+ and Cu2+ synergistically enhance the S100A13–FGF-1 interaction: Ca2+ alone increases binding affinity (EC50 ~10 µM); Cu2+ alone has no effect but markedly potentiates Ca2+-enhanced binding (EC50 ~50 nM); amlexanox abolishes the Cu2+-induced potentiation; this synergistic interaction is proposed as the initial step in non-classical FGF-1 release.","method":"Quartz crystal microbalance (real-time binding assay) with Strep-tagII-S100A13 and GST-FGF1, pharmacological inhibition with amlexanox","journal":"Neurochemistry international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct real-time binding measurement with pharmacological validation, single lab, two orthogonal approaches","pmids":["18164517"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of Ca2+-bound human S100A13 at 2.0 Å resolution reveals a homodimer with four EF-hand motifs; all alpha-helices are amphiphilic (unique among S100 family members), a feature proposed to relate to its ability to mediate FGF-1 and IL-1α release.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure, independently replicated by another crystal structure paper (PMID:18259052)","pmids":["17374362","18259052"],"is_preprint":false},{"year":2010,"finding":"The molecular interface between amlexanox and S100A13 was determined: amlexanox binds specifically to the FGF-1-binding site on S100A13, preventing formation of the FGF-1-S100A13 release complex and acting as an antagonist of non-classical FGF-1 secretion.","method":"3D solution structure by multidimensional NMR spectroscopy, ITC, fluorescence spectrophotometry","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR solution structure with ITC and fluorescence validation, mechanistic conclusion directly supported by structural data","pmids":["20178375"],"is_preprint":false},{"year":2010,"finding":"S100A13 is required for non-classical release of prothymosin-α (ProTα): S100A13 and ProTα are co-released upon ischemic/serum-deprivation stress; the Ca2+-dependent interaction requires the C-terminal peptide sequences of both proteins; a Δ88–98 S100A13 mutant blocks ProTα release but not S100A13 release; caspase-3 cleavage of ProTα removes its S100A13-interaction domain, preventing extracellular release during apoptosis.","method":"Immunoprecipitation, Co-release assay in C6 glioma cells, dominant-negative S100A13 mutant, caspase-3 cleavage analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-immunoprecipitation, dominant-negative mutant, caspase cleavage validation, multiple orthogonal approaches in single study","pmids":["20467443"],"is_preprint":false},{"year":2011,"finding":"The IL-1α–S100A13 tetrameric complex structure was determined: IL-1α and S100A13 form a heterotetrameric complex that is a key intermediate in the non-classical (ER/Golgi-independent) pathway for IL-1α secretion.","method":"Structural determination of the IL-1α–S100A13 complex (NMR/biophysical methods implied), complex characterization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural characterization of complex, single lab, method detail limited in abstract","pmids":["21270123"],"is_preprint":false},{"year":2009,"finding":"S100A13 forms a binary complex with the C2A domain of synaptotagmin-1 (Syt1); the S100A13–C2A complex acts as a template for FGF-1 dimerization and multiprotein complex formation in the non-classical FGF-1 release pathway.","method":"1H-15N HSQC NMR titration, 3D-filtered NOESY NMR, binary complex structure determination","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR solution structure determination, single lab, structural evidence is strong but functional consequence inferred from structural data","pmids":["19284995"],"is_preprint":false},{"year":2009,"finding":"S100A13 and FGF-1 can be exported in fully folded conformation: DHFR-fusion chimeras of both proteins were released despite treatment with aminopterin (which locks DHFR in folded state), demonstrating that folded tertiary structure does not prevent non-classical export.","method":"DHFR chimera expression in cells, aminopterin treatment, conditioned medium analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional experiment with folding-locked chimeras, single lab, single method","pmids":["19233122"],"is_preprint":false},{"year":2014,"finding":"S100A13 interacts with the C2 domain of RAGE with moderate affinity (Kd ~1.3 µM); the solution structure of the S100A13–RAGE C2 complex was solved by NMR, defining the interface regions on S100A13.","method":"NMR solution structure determination, isothermal titration calorimetry","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structure plus ITC binding measurement, single lab, functional consequence of RAGE interaction not directly demonstrated","pmids":["24982031"],"is_preprint":false},{"year":2019,"finding":"S100A13 promotes the non-classical secretion of IL-1α to the cell surface, thereby elevating NF-κB activity and inducing SASP gene expression; S100A13 knockdown reduces surface IL-1α, NF-κB activity, and SASP production; S100A13 overexpression accelerates oncogene Ras-induced senescence, drug-induced senescence, and replicative senescence; Cu2+ elevation during senescence enhances this pathway; S100A13 modulates senescence mediators p38, γ-H2AX, and mTORC1.","method":"S100A13 overexpression and knockdown in cell lines, surface IL-1α measurement, NF-κB reporter assay, SASP gene expression, Cu2+ chelation, multiple senescence models","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic manipulations (OE and KD) with defined pathway readouts in multiple senescence models, single lab","pmids":["30670674"],"is_preprint":false},{"year":2010,"finding":"S100A13 knockdown by RNAi in HUVECs blocked FGF-1 release from serum-deprived cells but did not affect FGF-1 intracellular transport (cytoplasm to membrane), demonstrating S100A13 is specifically required for the final release step, not intracellular trafficking.","method":"Lentiviral shRNA knockdown, immunofluorescence, western blot of conditioned medium in HUVECs","journal":"Journal of the Formosan Medical Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with specific subcellular phenotype dissection, single lab, two orthogonal readouts","pmids":["20863990"],"is_preprint":false},{"year":2020,"finding":"The stress-induced non-classical release of S100A13 and ProTα requires SNARE protein-mediated membrane tethering: p40 synaptotagmin-1 (Syt1) forms a Ca2+-dependent hetero-oligomeric complex with S100A13 (confirmed by pull-down and SPR); antibody-mediated intracellular blockade of Syt1 inhibits ProTα and S100A13 release; botulinum neurotoxin/C1 (cleaving syntaxin-1) and anti-syntaxin-1 antibody/siRNA block release of Syt1, S100A13 and ProTα.","method":"Pull-down assay, surface plasmon resonance, immunoprecipitation of conditioned medium, in situ proximity ligation assay, intracellular antibody delivery, BoNT/C1 treatment, siRNA knockdown, immunocytochemistry","journal":"Cellular and molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (SPR, PLA, pull-down, genetic and pharmacological SNARE disruption) establishing SNARE dependence, single lab but very rigorous","pmids":["32856232"],"is_preprint":false},{"year":2007,"finding":"S100A13 knockdown by RNAi (50–80% depletion) in highly invasive lung cancer cell lines reduced their in vitro invasive potential by 50–80%, without affecting proliferation; conversely, S100A13 overexpression in less invasive lines did not increase invasion, indicating S100A13 is required for but insufficient alone to induce invasion.","method":"RNAi knockdown, in vitro Matrigel invasion assay, transient overexpression, proliferation assay","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific phenotypic readout, gain-of-function as negative control, single lab","pmids":["18061437"],"is_preprint":false},{"year":2016,"finding":"S100A13 knockdown in thyroid cancer cells inhibited proliferation and invasion; HMGA1 was identified as a downstream effector of S100A13 in this context; S100A13 and HMGA1 expression are positively correlated in thyroid cancer tissue; overexpression of S100A13 increased tumor growth in xenograft models.","method":"Lentiviral S100A13 knockdown, siRNA-mediated HMGA1 knockdown, MTT, colony formation, Transwell invasion assays, nude mouse xenograft, tissue microarray","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and in vivo xenograft, HMGA1 pathway placement by siRNA, single lab","pmids":["27008379"],"is_preprint":false},{"year":2019,"finding":"Digenic inheritance of mutations in S100A3 and S100A13 causes familial pulmonary fibrosis; patient-derived fibroblasts with reduced S100A13 expression show aberrant intracellular calcium homeostasis, mitochondrial dysregulation, and altered ECM component expression.","method":"Molecular genetic analysis (sequencing), patient-derived fibroblast analysis, calcium homeostasis assays, mitochondrial function assays","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics combined with patient-derived cell functional analysis, two orthogonal readouts, but digenic so S100A13-specific contribution uncertain","pmids":["31073086"],"is_preprint":false},{"year":2023,"finding":"Reintroduction of wild-type S100A13 (and S100A3) into patient-derived fibroblasts (or control cells transfected with mutant constructs) restores receptor-mediated calcium signaling, reverses increased mitochondrial mass and hyperpolarization, and reduces inflammatory mediator secretion; extracellular recombinant S100A13 protein is sufficient to normalize these responses.","method":"Transfection of WT vs. mutant constructs, extracellular recombinant protein treatment, calcium signaling assays, mitochondrial mass/membrane potential measurements, inflammatory mediator quantification","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment with WT protein in patient-derived cells plus extracellular protein treatment, single lab, but contributions of S100A13 vs S100A3 are entangled","pmids":["38099297"],"is_preprint":false},{"year":2021,"finding":"TEAD4 directly binds the promoter of S100A13 transcript ENST00000440685 and activates its transcription; S100A13 knockdown increases cisplatin sensitivity in OSCC cells, while overexpression decreases it; S100A13 knockdown partially abrogates TEAD4-mediated cisplatin resistance.","method":"Luciferase reporter assay (TEAD4 binding to S100A13 promoter), RNAi knockdown, overexpression, cisplatin sensitivity assays, colony formation, apoptosis analysis","journal":"Journal of oral pathology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by luciferase assay, epistasis via knockdown/OE, single lab","pmids":["34358353"],"is_preprint":false},{"year":2026,"finding":"SP1 transcription factor directly binds the S100A13 promoter and activates its transcription, as demonstrated by luciferase reporter assay; S100A13 promotes osteosarcoma cell migration and invasion in functional assays.","method":"Luciferase reporter assay, wound-healing assay, Transwell invasion assay","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per finding, no additional validation of SP1-S100A13 axis","pmids":["41787040"],"is_preprint":false}],"current_model":"S100A13 is a homodimeric EF-hand Ca2+-binding protein (crystal structure solved at 1.8–2.0 Å) that functions as a critical cargo molecule in the non-classical (ER/Golgi-independent) secretion of signal peptide-less proteins: it forms Ca2+- and Cu2+-dependent multiprotein complexes with FGF-1, the C2A domain of p40 synaptotagmin-1, and IL-1α (and also with prothymosin-α), and facilitates their stress-induced export through the plasma membrane via a SNARE-dependent mechanism; the anti-allergic drug amlexanox blocks this pathway by binding the FGF-1-interaction site on S100A13; additionally, S100A13 promotes cellular senescence via IL-1α surface presentation and NF-κB/SASP activation, interacts with the RAGE C2 domain, regulates intracellular calcium homeostasis and mitochondrial function (loss-of-function mutations cause familial pulmonary fibrosis), and its transcription is regulated by TEAD4 and SP1."},"narrative":{"mechanistic_narrative":"S100A13 is a homodimeric EF-hand Ca2+-binding protein that functions as a core cargo/chaperone component of the non-classical (ER/Golgi-independent) secretion machinery for signal peptide-less proteins, exporting them across the plasma membrane in response to cellular stress [PMID:11410600, PMID:12746488, PMID:20467443]. Each dimer binds four Ca2+ with positive cooperativity, and Ca2+ binding drives conformational changes; unusually among S100 proteins, S100A13 does not expose a hydrophobic surface upon Ca2+ binding, and all of its alpha-helices are amphiphilic, a feature linked to its release-mediating activity [PMID:10722710, PMID:17374362, PMID:18259052]. It additionally binds Cu2+ independently of Ca2+, with the two ions acting synergistically to potentiate cargo engagement: Ca2+ and Cu2+ together markedly enhance the S100A13–FGF-1 interaction and promote FGF-1 homodimerization required for export [PMID:16766622, PMID:18164517]. Mechanistically, S100A13 nucleates a multiprotein release complex—forming a binary complex with the C2A domain of p40 synaptotagmin-1 that templates FGF-1 dimerization, and engaging cargo through its basic C-terminal peptide; deletion of residues 88–98 yields a dominant-negative that selectively blocks cargo release while permitting S100A13's own export [PMID:16519964, PMID:20467443, PMID:19284995]. The same module exports IL-1α (Cu2+-dependently, via a heterotetrameric IL-1α–S100A13 intermediate) and prothymosin-α, whose caspase-3 cleavage removes the S100A13-interaction domain and aborts release during apoptosis [PMID:12746488, PMID:20467443, PMID:21270123]. Stress-induced export is completed by SNARE-dependent membrane tethering, requiring a Ca2+-dependent S100A13–synaptotagmin-1 hetero-oligomer and syntaxin-1 [PMID:32856232], and S100A13 acts specifically at this final release step rather than in intracellular trafficking [PMID:20863990]. The anti-allergic drug amlexanox antagonizes the pathway by binding the FGF-1-interaction site on S100A13 [PMID:20178375]. Through IL-1α surface presentation, S100A13 elevates NF-κB activity and induces the senescence-associated secretory phenotype, accelerating cellular senescence [PMID:30670674], and it also engages the C2 domain of RAGE [PMID:24982031]. Digenic mutations in S100A13 (with S100A3) cause familial pulmonary fibrosis, with patient fibroblasts showing aberrant calcium homeostasis and mitochondrial dysregulation that are rescued by wild-type or recombinant extracellular S100A13 [PMID:31073086, PMID:38099297].","teleology":[{"year":1998,"claim":"Established S100A13 as a physical component of the FGF-1 non-classical release machinery, answering whether any dedicated factor accompanies signal-peptide-less FGF-1 export.","evidence":"Purification of a brain-derived FGF-1/p40 synaptotagmin-1 complex plus amlexanox inhibition of stress-induced release in cells","pmids":["9712836"],"confidence":"Medium","gaps":["Did not define which S100A13 region contacts cargo","Functional necessity of S100A13 not yet tested by loss-of-function"]},{"year":2000,"claim":"Defined the biophysical and structural baseline—homodimer, cooperative four-Ca2+ binding, and an atypical absence of Ca2+-induced hydrophobic exposure—distinguishing S100A13 from canonical S100 proteins.","evidence":"Flow dialysis, fluorescence, circular dichroism, and immunofluorescence in multiple cell types","pmids":["10722710"],"confidence":"High","gaps":["How the unusual surface chemistry relates to cargo export untested at this stage","Cu2+ binding not yet examined"]},{"year":2001,"claim":"Showed S100A13 is functionally required for FGF-1 release and mapped the requirement to its basic C-terminal domain, advancing from correlation to causal mechanism.","evidence":"Wild-type overexpression, C-terminal-deletion dominant-negative, and Cys-free FGF-1 rescue in NIH 3T3 cells","pmids":["11410600"],"confidence":"High","gaps":["Did not resolve the molecular interface or stoichiometry of the cargo complex","Membrane translocation step not addressed"]},{"year":2003,"claim":"Generalized S100A13 cargo function beyond FGF-1 to IL-1α and revealed copper-dependence of cargo engagement.","evidence":"Co-immunoprecipitation, dominant-negative mutant, and Cu2+ chelation in U937 and NIH 3T3 cells","pmids":["12746488"],"confidence":"High","gaps":["Structural basis of the Cu2+-dependent IL-1α interaction not defined here","Cu2+ binding site on S100A13 unmapped"]},{"year":2006,"claim":"Quantified independent Ca2+ and Cu2+ binding and connected Cu2+ to FGF-1 dimerization, explaining the metal requirement of the release pathway.","evidence":"ITC, multidimensional NMR, terbium binding, thermal denaturation, and H/D exchange","pmids":["16766622","18164517"],"confidence":"High","gaps":["Did not establish whether metal effects operate identically for non-FGF-1 cargoes"]},{"year":2007,"claim":"Resolved the crystal structure and the lipid-binding behavior, linking amphiphilic helices and apo-form phosphatidylserine binding to a model of membrane translocation.","evidence":"X-ray crystallography at 2.0 Å and biophysical lipid-vesicle binding assays (ITC, ANS, CD)","pmids":["17374362","18259052","17991455"],"confidence":"High","gaps":["Membrane translocation role of lipid binding inferred, not directly demonstrated in cells"]},{"year":2009,"claim":"Defined the S100A13–synaptotagmin-1 C2A binary complex as the template for FGF-1 dimerization and showed cargo is exported in a folded state.","evidence":"NMR titration/NOESY structure of the binary complex and DHFR folding-locked chimera export assays","pmids":["19284995","19233122"],"confidence":"Medium","gaps":["Functional consequence of the binary complex inferred from structure","Mechanism by which a folded protein crosses the bilayer unresolved"]},{"year":2010,"claim":"Pinpointed amlexanox to the FGF-1-binding site and demonstrated, by RNAi, that S100A13 acts at the terminal release step rather than intracellular trafficking; extended the cargo repertoire to prothymosin-α with caspase-3-gated control.","evidence":"NMR solution structure with ITC/fluorescence, lentiviral shRNA in HUVECs, and co-release/dominant-negative/caspase assays in glioma cells","pmids":["20178375","20863990","20467443"],"confidence":"High","gaps":["Membrane-crossing step still mechanistically undefined","How cargo selectivity is achieved across FGF-1/IL-1α/ProTα not unified"]},{"year":2011,"claim":"Provided structural evidence for an IL-1α–S100A13 heterotetramer as the secretion intermediate.","evidence":"Structural characterization of the IL-1α–S100A13 complex","pmids":["21270123"],"confidence":"Medium","gaps":["Method detail limited","In vivo relevance of the tetramer not tested"]},{"year":2014,"claim":"Identified a moderate-affinity S100A13–RAGE C2 interaction and mapped its interface, raising a potential receptor-engagement role distinct from cargo export.","evidence":"NMR solution structure and ITC","pmids":["24982031"],"confidence":"Medium","gaps":["Functional/cellular consequence of RAGE binding not demonstrated"]},{"year":2019,"claim":"Connected S100A13-driven IL-1α surface presentation to NF-κB/SASP activation and senescence, giving the secretion pathway a physiological output.","evidence":"Overexpression/knockdown with surface IL-1α, NF-κB reporter, SASP readouts and Cu2+ chelation across multiple senescence models","pmids":["30670674"],"confidence":"Medium","gaps":["Single lab","Direct contribution of senescence pathway to organismal phenotypes untested"]},{"year":2020,"claim":"Established SNARE dependence of the export step, showing syntaxin-1 and a Ca2+-dependent synaptotagmin-1–S100A13 hetero-oligomer are required for membrane tethering and release.","evidence":"Pull-down, SPR, PLA, intracellular antibody blockade, BoNT/C1, and siRNA in neural cells","pmids":["32856232"],"confidence":"High","gaps":["Whether identical SNARE machinery operates for FGF-1 and IL-1α in non-neural cells not shown"]},{"year":2019,"claim":"Linked S100A13 loss-of-function to familial pulmonary fibrosis with calcium/mitochondrial dysfunction, and later demonstrated rescue by wild-type and extracellular recombinant protein, establishing disease causality and reversibility.","evidence":"Patient genetics and fibroblast assays; transfection rescue and extracellular protein treatment with calcium/mitochondrial/inflammatory readouts","pmids":["31073086","38099297"],"confidence":"Medium","gaps":["Digenic with S100A3, so S100A13-specific contribution entangled","Mechanism linking secretion function to mitochondrial/calcium phenotypes unclear"]},{"year":2021,"claim":"Placed S100A13 under transcriptional control of TEAD4 and SP1 and connected its expression to cancer cell invasion and chemoresistance.","evidence":"Luciferase promoter assays, RNAi/overexpression, cisplatin sensitivity, invasion and xenograft assays across OSCC, thyroid, lung and osteosarcoma models","pmids":["34358353","27008379","18061437","41787040"],"confidence":"Medium","gaps":["Whether cancer phenotypes depend on the secretion function or another activity unresolved","SP1 axis (osteosarcoma) is single-method, Low confidence"]},{"year":null,"claim":"The physical mechanism by which the S100A13 complex translocates folded cargo across an intact plasma membrane—and how a single module selects among FGF-1, IL-1α, and prothymosin-α—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted membrane-translocation system","Cargo-selection determinants not defined","Unified model linking secretion, senescence, fibrosis and cancer phenotypes absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,2,7,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,12,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17,19]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,12]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,7,12,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[17]}],"complexes":["S100A13–FGF-1–p40 synaptotagmin-1 release complex","IL-1α–S100A13 heterotetramer","S100A13–prothymosin-α complex"],"partners":["FGF1","SYT1","IL1A","PTMA","STX1A","AGER","S100A3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99584","full_name":"Protein S100-A13","aliases":["S100 calcium-binding protein A13"],"length_aa":98,"mass_kda":11.5,"function":"Plays a role in the export of proteins that lack a signal peptide and are secreted by an alternative pathway. Binds two calcium ions per subunit. Binds one copper ion. Binding of one copper ion does not interfere with calcium binding. Required for the copper-dependent stress-induced export of IL1A and FGF1. The calcium-free protein binds to lipid vesicles containing phosphatidylserine, but not to vesicles containing phosphatidylcholine (By similarity)","subcellular_location":"Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/Q99584/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S100A13","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSPA14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/S100A13","total_profiled":1310},"omim":[{"mim_id":"617437","title":"S100 CALCIUM-BINDING PROTEIN A16; S100A16","url":"https://www.omim.org/entry/617437"},{"mim_id":"607986","title":"S100 CALCIUM-BINDING PROTEIN A14; S100A14","url":"https://www.omim.org/entry/607986"},{"mim_id":"606083","title":"POLYBROMO 1; PBRM1","url":"https://www.omim.org/entry/606083"},{"mim_id":"601989","title":"S100 CALCIUM-BINDING PROTEIN A13; S100A13","url":"https://www.omim.org/entry/601989"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/S100A13"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q99584","domains":[{"cath_id":"1.10.238.10","chopping":"14-96","consensus_level":"high","plddt":81.7335,"start":14,"end":96}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99584","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99584-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99584-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S100A13","jax_strain_url":"https://www.jax.org/strain/search?query=S100A13"},"sequence":{"accession":"Q99584","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99584.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99584/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99584"}},"corpus_meta":[{"pmid":"9712836","id":"PMC_9712836","title":"S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9712836","citation_count":103,"is_preprint":false},{"pmid":"12746488","id":"PMC_12746488","title":"S100A13 mediates the copper-dependent stress-induced release of IL-1alpha from both human U937 and murine NIH 3T3 cells.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12746488","citation_count":81,"is_preprint":false},{"pmid":"10051426","id":"PMC_10051426","title":"Three distinct anti-allergic drugs, amlexanox, cromolyn and tranilast, bind to S100A12 and S100A13 of the S100 protein family.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10051426","citation_count":76,"is_preprint":false},{"pmid":"11410600","id":"PMC_11410600","title":"S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11410600","citation_count":73,"is_preprint":false},{"pmid":"8878558","id":"PMC_8878558","title":"Characterization of the human and mouse cDNAs coding for S100A13, a new member of the S100 protein family.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8878558","citation_count":61,"is_preprint":false},{"pmid":"20208480","id":"PMC_20208480","title":"S100A13 is a new angiogenic marker in human melanoma.","date":"2010","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/20208480","citation_count":59,"is_preprint":false},{"pmid":"10722710","id":"PMC_10722710","title":"S100A13. 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/18259052","citation_count":11,"is_preprint":false},{"pmid":"34358353","id":"PMC_34358353","title":"Systematic screening identifies a TEAD4-S100A13 axis modulating cisplatin sensitivity of oral squamous cell carcinoma cells.","date":"2021","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34358353","citation_count":9,"is_preprint":false},{"pmid":"32493412","id":"PMC_32493412","title":"Genome-wide analysis of DNA methylation identifies S100A13 as an epigenetic biomarker in individuals with chronic (≥ 30 years) type 2 diabetes without diabetic retinopathy.","date":"2020","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32493412","citation_count":9,"is_preprint":false},{"pmid":"17374362","id":"PMC_17374362","title":"Crystal structure study on human S100A13 at 2.0 A resolution.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17374362","citation_count":9,"is_preprint":false},{"pmid":"20863990","id":"PMC_20863990","title":"Effect of human S100A13 gene silencing on FGF-1 transportation in human endothelial cells.","date":"2010","source":"Journal of the Formosan Medical Association = Taiwan yi zhi","url":"https://pubmed.ncbi.nlm.nih.gov/20863990","citation_count":7,"is_preprint":false},{"pmid":"19284995","id":"PMC_19284995","title":"S100A13-C2A binary complex structure-a key component in the acidic fibroblast growth factor for the non-classical pathway.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19284995","citation_count":6,"is_preprint":false},{"pmid":"38099297","id":"PMC_38099297","title":"Wild-type S100A3 and S100A13 restore calcium homeostasis and mitigate mitochondrial dysregulation in pulmonary fibrosis patient-derived cells.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38099297","citation_count":3,"is_preprint":false},{"pmid":"32856232","id":"PMC_32856232","title":"Involvement of SNARE Protein Interaction for Non-classical Release of DAMPs/Alarmins Proteins, Prothymosin Alpha and S100A13.","date":"2020","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/32856232","citation_count":2,"is_preprint":false},{"pmid":"18710615","id":"PMC_18710615","title":"[Overexpressing exogenous S100A13 gene and its effect on proliferation of human thyroid cancer cell line TT].","date":"2008","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18710615","citation_count":2,"is_preprint":false},{"pmid":"17077500","id":"PMC_17077500","title":"Crystallization and preliminary X-ray analysis of human S100A13.","date":"2006","source":"Acta crystallographica. 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a deletion mutant of S100A13 lacking its basic residue-rich C-terminal domain acts as a dominant-negative inhibitor of FGF-1 release; S100A13 expression also enables release of a normally non-releasable Cys-free FGF-1 mutant.\",\n      \"method\": \"Overexpression and dominant-negative deletion mutant studies in NIH 3T3 cells, conditioned medium analysis, ammonium sulfate solubility assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods (WT overexpression, dominant-negative mutant, Cys-free FGF-1 rescue), replicated functional readout\",\n      \"pmids\": [\"11410600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"S100A13 mediates the copper-dependent, stress-induced non-classical release of IL-1α: IL-1α associates intracellularly with S100A13 in a Cu2+-dependent manner; a dominant-negative S100A13 mutant (lacking its novel sequence) represses IL-1α export; wild-type S100A13 overexpression eliminates the requirement for stress-induced transcription for IL-1α release.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative S100A13 mutant expression, conditioned medium western blot in U937 and NIH 3T3 cells, Cu2+ chelation experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction, dominant-negative genetic approach, copper chelation pharmacology, two cell lines, multiple orthogonal methods\",\n      \"pmids\": [\"12746488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"S100A13 (and S100A12) directly bind the anti-allergic drugs amlexanox, cromolyn, and tranilast, as demonstrated by affinity chromatography; this binding is calcium-sensitive and distinct from calmodulin interactions.\",\n      \"method\": \"Drug-coupled affinity chromatography, reversed-phase HPLC, cDNA sequencing of isolated proteins, binding confirmed with recombinant protein\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography with recombinant protein validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"10051426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human recombinant S100A13 is a homodimer that binds four Ca2+ per dimer in two sets of sites with positive cooperativity (high- and low-affinity); Ca2+ binding causes conformational changes detectable by fluorescence and CD; S100A13 uniquely does not expose hydrophobic patches upon Ca2+ binding (unlike most S100 proteins); in human smooth muscle cells, S100A13 localizes to the perinuclear area, distinct from S100A2 (nuclear) and S100A1 (stress fibers).\",\n      \"method\": \"Flow dialysis, fluorescence spectrophotometry, circular dichroism, immunofluorescence with specific antisera in multiple cell types\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical characterization with multiple orthogonal biophysical methods plus cell localization; rigorous single-study approach\",\n      \"pmids\": [\"10722710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"S100A13 undergoes Ca2+-dependent translocation in endothelial cells via the classical Golgi-ER pathway in response to angiotensin II stimulation, a pathway distinct from S100A6 (which uses actin stress fibers).\",\n      \"method\": \"Live cell imaging/translocation assays in endothelial cells, pharmacological disruption of Golgi-ER and actin pathways\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization experiment with functional pathway discrimination, single lab, pharmacological and imaging methods\",\n      \"pmids\": [\"12118070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"S100A13 binds Cu2+ and Ca2+ independently with similar micromolar affinity (two atoms per subunit); Ca2+ stabilizes S100A13 while Cu2+ destabilizes it; S100A13 can bind both ions simultaneously; Cu2+ binding is important for FGF-1 homodimer formation and subsequent non-classical secretion.\",\n      \"method\": \"Isothermal titration calorimetry, multidimensional NMR spectroscopy, terbium binding, thermal denaturation by far-UV CD, limited trypsin digestion, hydrogen-deuterium exchange\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods including NMR and ITC, rigorous single-study approach\",\n      \"pmids\": [\"16766622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FGF-1 and S100A13 are co-released from astrocytes upon serum-deprivation stress via a non-vesicular (Brefeldin A-insensitive) pathway; S100A13 is the major protein co-immunoprecipitated with FGF-1; the interaction requires the C-terminal 11 amino acid peptide of S100A13 and is Ca2+-sensitive; a Δ88–98 S100A13 mutant selectively blocks FGF-1 release but not S100A13 release itself; amlexanox blocks both; Ca2+ chelation (BAPTA-AM) abolishes both releases.\",\n      \"method\": \"Immunocytochemistry, immunoblot of conditioned medium, immunoprecipitation, GST/Strep-tag pull-down with deletion mutants, pharmacological inhibition (amlexanox, BAPTA-AM, Brefeldin A), Ca2+ imaging\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown, deletion mutant dominant-negative, Ca2+ imaging, pharmacological validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"16519964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ApoS100A13 (calcium-free form) preferentially binds phosphatidylserine lipid vesicles; Ca2+-bound S100A13 binds weakly; apoS100A13 undergoes subtle conformational change exposing hydrophobic surfaces upon lipid binding; these lipid interactions are proposed to facilitate membrane translocation during non-classical FGF-1 secretion.\",\n      \"method\": \"Isothermal titration calorimetry, steady-state fluorescence, equilibrium thermal unfolding, ANS binding, limited trypsin digestion, far-UV CD with phosphatidylserine SUVs\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical in vitro methods, single lab, functional interpretation inferred but not directly demonstrated\",\n      \"pmids\": [\"17991455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ca2+ and Cu2+ synergistically enhance the S100A13–FGF-1 interaction: Ca2+ alone increases binding affinity (EC50 ~10 µM); Cu2+ alone has no effect but markedly potentiates Ca2+-enhanced binding (EC50 ~50 nM); amlexanox abolishes the Cu2+-induced potentiation; this synergistic interaction is proposed as the initial step in non-classical FGF-1 release.\",\n      \"method\": \"Quartz crystal microbalance (real-time binding assay) with Strep-tagII-S100A13 and GST-FGF1, pharmacological inhibition with amlexanox\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct real-time binding measurement with pharmacological validation, single lab, two orthogonal approaches\",\n      \"pmids\": [\"18164517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of Ca2+-bound human S100A13 at 2.0 Å resolution reveals a homodimer with four EF-hand motifs; all alpha-helices are amphiphilic (unique among S100 family members), a feature proposed to relate to its ability to mediate FGF-1 and IL-1α release.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure, independently replicated by another crystal structure paper (PMID:18259052)\",\n      \"pmids\": [\"17374362\", \"18259052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The molecular interface between amlexanox and S100A13 was determined: amlexanox binds specifically to the FGF-1-binding site on S100A13, preventing formation of the FGF-1-S100A13 release complex and acting as an antagonist of non-classical FGF-1 secretion.\",\n      \"method\": \"3D solution structure by multidimensional NMR spectroscopy, ITC, fluorescence spectrophotometry\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR solution structure with ITC and fluorescence validation, mechanistic conclusion directly supported by structural data\",\n      \"pmids\": [\"20178375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A13 is required for non-classical release of prothymosin-α (ProTα): S100A13 and ProTα are co-released upon ischemic/serum-deprivation stress; the Ca2+-dependent interaction requires the C-terminal peptide sequences of both proteins; a Δ88–98 S100A13 mutant blocks ProTα release but not S100A13 release; caspase-3 cleavage of ProTα removes its S100A13-interaction domain, preventing extracellular release during apoptosis.\",\n      \"method\": \"Immunoprecipitation, Co-release assay in C6 glioma cells, dominant-negative S100A13 mutant, caspase-3 cleavage analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-immunoprecipitation, dominant-negative mutant, caspase cleavage validation, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"20467443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The IL-1α–S100A13 tetrameric complex structure was determined: IL-1α and S100A13 form a heterotetrameric complex that is a key intermediate in the non-classical (ER/Golgi-independent) pathway for IL-1α secretion.\",\n      \"method\": \"Structural determination of the IL-1α–S100A13 complex (NMR/biophysical methods implied), complex characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural characterization of complex, single lab, method detail limited in abstract\",\n      \"pmids\": [\"21270123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S100A13 forms a binary complex with the C2A domain of synaptotagmin-1 (Syt1); the S100A13–C2A complex acts as a template for FGF-1 dimerization and multiprotein complex formation in the non-classical FGF-1 release pathway.\",\n      \"method\": \"1H-15N HSQC NMR titration, 3D-filtered NOESY NMR, binary complex structure determination\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR solution structure determination, single lab, structural evidence is strong but functional consequence inferred from structural data\",\n      \"pmids\": [\"19284995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S100A13 and FGF-1 can be exported in fully folded conformation: DHFR-fusion chimeras of both proteins were released despite treatment with aminopterin (which locks DHFR in folded state), demonstrating that folded tertiary structure does not prevent non-classical export.\",\n      \"method\": \"DHFR chimera expression in cells, aminopterin treatment, conditioned medium analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional experiment with folding-locked chimeras, single lab, single method\",\n      \"pmids\": [\"19233122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"S100A13 interacts with the C2 domain of RAGE with moderate affinity (Kd ~1.3 µM); the solution structure of the S100A13–RAGE C2 complex was solved by NMR, defining the interface regions on S100A13.\",\n      \"method\": \"NMR solution structure determination, isothermal titration calorimetry\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus ITC binding measurement, single lab, functional consequence of RAGE interaction not directly demonstrated\",\n      \"pmids\": [\"24982031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S100A13 promotes the non-classical secretion of IL-1α to the cell surface, thereby elevating NF-κB activity and inducing SASP gene expression; S100A13 knockdown reduces surface IL-1α, NF-κB activity, and SASP production; S100A13 overexpression accelerates oncogene Ras-induced senescence, drug-induced senescence, and replicative senescence; Cu2+ elevation during senescence enhances this pathway; S100A13 modulates senescence mediators p38, γ-H2AX, and mTORC1.\",\n      \"method\": \"S100A13 overexpression and knockdown in cell lines, surface IL-1α measurement, NF-κB reporter assay, SASP gene expression, Cu2+ chelation, multiple senescence models\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic manipulations (OE and KD) with defined pathway readouts in multiple senescence models, single lab\",\n      \"pmids\": [\"30670674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A13 knockdown by RNAi in HUVECs blocked FGF-1 release from serum-deprived cells but did not affect FGF-1 intracellular transport (cytoplasm to membrane), demonstrating S100A13 is specifically required for the final release step, not intracellular trafficking.\",\n      \"method\": \"Lentiviral shRNA knockdown, immunofluorescence, western blot of conditioned medium in HUVECs\",\n      \"journal\": \"Journal of the Formosan Medical Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with specific subcellular phenotype dissection, single lab, two orthogonal readouts\",\n      \"pmids\": [\"20863990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The stress-induced non-classical release of S100A13 and ProTα requires SNARE protein-mediated membrane tethering: p40 synaptotagmin-1 (Syt1) forms a Ca2+-dependent hetero-oligomeric complex with S100A13 (confirmed by pull-down and SPR); antibody-mediated intracellular blockade of Syt1 inhibits ProTα and S100A13 release; botulinum neurotoxin/C1 (cleaving syntaxin-1) and anti-syntaxin-1 antibody/siRNA block release of Syt1, S100A13 and ProTα.\",\n      \"method\": \"Pull-down assay, surface plasmon resonance, immunoprecipitation of conditioned medium, in situ proximity ligation assay, intracellular antibody delivery, BoNT/C1 treatment, siRNA knockdown, immunocytochemistry\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (SPR, PLA, pull-down, genetic and pharmacological SNARE disruption) establishing SNARE dependence, single lab but very rigorous\",\n      \"pmids\": [\"32856232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"S100A13 knockdown by RNAi (50–80% depletion) in highly invasive lung cancer cell lines reduced their in vitro invasive potential by 50–80%, without affecting proliferation; conversely, S100A13 overexpression in less invasive lines did not increase invasion, indicating S100A13 is required for but insufficient alone to induce invasion.\",\n      \"method\": \"RNAi knockdown, in vitro Matrigel invasion assay, transient overexpression, proliferation assay\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific phenotypic readout, gain-of-function as negative control, single lab\",\n      \"pmids\": [\"18061437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S100A13 knockdown in thyroid cancer cells inhibited proliferation and invasion; HMGA1 was identified as a downstream effector of S100A13 in this context; S100A13 and HMGA1 expression are positively correlated in thyroid cancer tissue; overexpression of S100A13 increased tumor growth in xenograft models.\",\n      \"method\": \"Lentiviral S100A13 knockdown, siRNA-mediated HMGA1 knockdown, MTT, colony formation, Transwell invasion assays, nude mouse xenograft, tissue microarray\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and in vivo xenograft, HMGA1 pathway placement by siRNA, single lab\",\n      \"pmids\": [\"27008379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Digenic inheritance of mutations in S100A3 and S100A13 causes familial pulmonary fibrosis; patient-derived fibroblasts with reduced S100A13 expression show aberrant intracellular calcium homeostasis, mitochondrial dysregulation, and altered ECM component expression.\",\n      \"method\": \"Molecular genetic analysis (sequencing), patient-derived fibroblast analysis, calcium homeostasis assays, mitochondrial function assays\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics combined with patient-derived cell functional analysis, two orthogonal readouts, but digenic so S100A13-specific contribution uncertain\",\n      \"pmids\": [\"31073086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reintroduction of wild-type S100A13 (and S100A3) into patient-derived fibroblasts (or control cells transfected with mutant constructs) restores receptor-mediated calcium signaling, reverses increased mitochondrial mass and hyperpolarization, and reduces inflammatory mediator secretion; extracellular recombinant S100A13 protein is sufficient to normalize these responses.\",\n      \"method\": \"Transfection of WT vs. mutant constructs, extracellular recombinant protein treatment, calcium signaling assays, mitochondrial mass/membrane potential measurements, inflammatory mediator quantification\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment with WT protein in patient-derived cells plus extracellular protein treatment, single lab, but contributions of S100A13 vs S100A3 are entangled\",\n      \"pmids\": [\"38099297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEAD4 directly binds the promoter of S100A13 transcript ENST00000440685 and activates its transcription; S100A13 knockdown increases cisplatin sensitivity in OSCC cells, while overexpression decreases it; S100A13 knockdown partially abrogates TEAD4-mediated cisplatin resistance.\",\n      \"method\": \"Luciferase reporter assay (TEAD4 binding to S100A13 promoter), RNAi knockdown, overexpression, cisplatin sensitivity assays, colony formation, apoptosis analysis\",\n      \"journal\": \"Journal of oral pathology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by luciferase assay, epistasis via knockdown/OE, single lab\",\n      \"pmids\": [\"34358353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SP1 transcription factor directly binds the S100A13 promoter and activates its transcription, as demonstrated by luciferase reporter assay; S100A13 promotes osteosarcoma cell migration and invasion in functional assays.\",\n      \"method\": \"Luciferase reporter assay, wound-healing assay, Transwell invasion assay\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per finding, no additional validation of SP1-S100A13 axis\",\n      \"pmids\": [\"41787040\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S100A13 is a homodimeric EF-hand Ca2+-binding protein (crystal structure solved at 1.8–2.0 Å) that functions as a critical cargo molecule in the non-classical (ER/Golgi-independent) secretion of signal peptide-less proteins: it forms Ca2+- and Cu2+-dependent multiprotein complexes with FGF-1, the C2A domain of p40 synaptotagmin-1, and IL-1α (and also with prothymosin-α), and facilitates their stress-induced export through the plasma membrane via a SNARE-dependent mechanism; the anti-allergic drug amlexanox blocks this pathway by binding the FGF-1-interaction site on S100A13; additionally, S100A13 promotes cellular senescence via IL-1α surface presentation and NF-κB/SASP activation, interacts with the RAGE C2 domain, regulates intracellular calcium homeostasis and mitochondrial function (loss-of-function mutations cause familial pulmonary fibrosis), and its transcription is regulated by TEAD4 and SP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"S100A13 is a homodimeric EF-hand Ca2+-binding protein that functions as a core cargo/chaperone component of the non-classical (ER/Golgi-independent) secretion machinery for signal peptide-less proteins, exporting them across the plasma membrane in response to cellular stress [#1, #2, #12]. Each dimer binds four Ca2+ with positive cooperativity, and Ca2+ binding drives conformational changes; unusually among S100 proteins, S100A13 does not expose a hydrophobic surface upon Ca2+ binding, and all of its alpha-helices are amphiphilic, a feature linked to its release-mediating activity [#4, #10]. It additionally binds Cu2+ independently of Ca2+, with the two ions acting synergistically to potentiate cargo engagement: Ca2+ and Cu2+ together markedly enhance the S100A13–FGF-1 interaction and promote FGF-1 homodimerization required for export [#6, #9]. Mechanistically, S100A13 nucleates a multiprotein release complex—forming a binary complex with the C2A domain of p40 synaptotagmin-1 that templates FGF-1 dimerization, and engaging cargo through its basic C-terminal peptide; deletion of residues 88–98 yields a dominant-negative that selectively blocks cargo release while permitting S100A13's own export [#7, #12, #14]. The same module exports IL-1α (Cu2+-dependently, via a heterotetrameric IL-1α–S100A13 intermediate) and prothymosin-α, whose caspase-3 cleavage removes the S100A13-interaction domain and aborts release during apoptosis [#2, #12, #13]. Stress-induced export is completed by SNARE-dependent membrane tethering, requiring a Ca2+-dependent S100A13–synaptotagmin-1 hetero-oligomer and syntaxin-1 [#19], and S100A13 acts specifically at this final release step rather than in intracellular trafficking [#18]. The anti-allergic drug amlexanox antagonizes the pathway by binding the FGF-1-interaction site on S100A13 [#11]. Through IL-1α surface presentation, S100A13 elevates NF-κB activity and induces the senescence-associated secretory phenotype, accelerating cellular senescence [#17], and it also engages the C2 domain of RAGE [#16]. Digenic mutations in S100A13 (with S100A3) cause familial pulmonary fibrosis, with patient fibroblasts showing aberrant calcium homeostasis and mitochondrial dysregulation that are rescued by wild-type or recombinant extracellular S100A13 [#22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established S100A13 as a physical component of the FGF-1 non-classical release machinery, answering whether any dedicated factor accompanies signal-peptide-less FGF-1 export.\",\n      \"evidence\": \"Purification of a brain-derived FGF-1/p40 synaptotagmin-1 complex plus amlexanox inhibition of stress-induced release in cells\",\n      \"pmids\": [\"9712836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which S100A13 region contacts cargo\", \"Functional necessity of S100A13 not yet tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the biophysical and structural baseline—homodimer, cooperative four-Ca2+ binding, and an atypical absence of Ca2+-induced hydrophobic exposure—distinguishing S100A13 from canonical S100 proteins.\",\n      \"evidence\": \"Flow dialysis, fluorescence, circular dichroism, and immunofluorescence in multiple cell types\",\n      \"pmids\": [\"10722710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the unusual surface chemistry relates to cargo export untested at this stage\", \"Cu2+ binding not yet examined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed S100A13 is functionally required for FGF-1 release and mapped the requirement to its basic C-terminal domain, advancing from correlation to causal mechanism.\",\n      \"evidence\": \"Wild-type overexpression, C-terminal-deletion dominant-negative, and Cys-free FGF-1 rescue in NIH 3T3 cells\",\n      \"pmids\": [\"11410600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular interface or stoichiometry of the cargo complex\", \"Membrane translocation step not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Generalized S100A13 cargo function beyond FGF-1 to IL-1α and revealed copper-dependence of cargo engagement.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative mutant, and Cu2+ chelation in U937 and NIH 3T3 cells\",\n      \"pmids\": [\"12746488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Cu2+-dependent IL-1α interaction not defined here\", \"Cu2+ binding site on S100A13 unmapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Quantified independent Ca2+ and Cu2+ binding and connected Cu2+ to FGF-1 dimerization, explaining the metal requirement of the release pathway.\",\n      \"evidence\": \"ITC, multidimensional NMR, terbium binding, thermal denaturation, and H/D exchange\",\n      \"pmids\": [\"16766622\", \"18164517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether metal effects operate identically for non-FGF-1 cargoes\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the crystal structure and the lipid-binding behavior, linking amphiphilic helices and apo-form phosphatidylserine binding to a model of membrane translocation.\",\n      \"evidence\": \"X-ray crystallography at 2.0 Å and biophysical lipid-vesicle binding assays (ITC, ANS, CD)\",\n      \"pmids\": [\"17374362\", \"18259052\", \"17991455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane translocation role of lipid binding inferred, not directly demonstrated in cells\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the S100A13–synaptotagmin-1 C2A binary complex as the template for FGF-1 dimerization and showed cargo is exported in a folded state.\",\n      \"evidence\": \"NMR titration/NOESY structure of the binary complex and DHFR folding-locked chimera export assays\",\n      \"pmids\": [\"19284995\", \"19233122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the binary complex inferred from structure\", \"Mechanism by which a folded protein crosses the bilayer unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pinpointed amlexanox to the FGF-1-binding site and demonstrated, by RNAi, that S100A13 acts at the terminal release step rather than intracellular trafficking; extended the cargo repertoire to prothymosin-α with caspase-3-gated control.\",\n      \"evidence\": \"NMR solution structure with ITC/fluorescence, lentiviral shRNA in HUVECs, and co-release/dominant-negative/caspase assays in glioma cells\",\n      \"pmids\": [\"20178375\", \"20863990\", \"20467443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane-crossing step still mechanistically undefined\", \"How cargo selectivity is achieved across FGF-1/IL-1α/ProTα not unified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural evidence for an IL-1α–S100A13 heterotetramer as the secretion intermediate.\",\n      \"evidence\": \"Structural characterization of the IL-1α–S100A13 complex\",\n      \"pmids\": [\"21270123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Method detail limited\", \"In vivo relevance of the tetramer not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a moderate-affinity S100A13–RAGE C2 interaction and mapped its interface, raising a potential receptor-engagement role distinct from cargo export.\",\n      \"evidence\": \"NMR solution structure and ITC\",\n      \"pmids\": [\"24982031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/cellular consequence of RAGE binding not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected S100A13-driven IL-1α surface presentation to NF-κB/SASP activation and senescence, giving the secretion pathway a physiological output.\",\n      \"evidence\": \"Overexpression/knockdown with surface IL-1α, NF-κB reporter, SASP readouts and Cu2+ chelation across multiple senescence models\",\n      \"pmids\": [\"30670674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct contribution of senescence pathway to organismal phenotypes untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established SNARE dependence of the export step, showing syntaxin-1 and a Ca2+-dependent synaptotagmin-1–S100A13 hetero-oligomer are required for membrane tethering and release.\",\n      \"evidence\": \"Pull-down, SPR, PLA, intracellular antibody blockade, BoNT/C1, and siRNA in neural cells\",\n      \"pmids\": [\"32856232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether identical SNARE machinery operates for FGF-1 and IL-1α in non-neural cells not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked S100A13 loss-of-function to familial pulmonary fibrosis with calcium/mitochondrial dysfunction, and later demonstrated rescue by wild-type and extracellular recombinant protein, establishing disease causality and reversibility.\",\n      \"evidence\": \"Patient genetics and fibroblast assays; transfection rescue and extracellular protein treatment with calcium/mitochondrial/inflammatory readouts\",\n      \"pmids\": [\"31073086\", \"38099297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Digenic with S100A3, so S100A13-specific contribution entangled\", \"Mechanism linking secretion function to mitochondrial/calcium phenotypes unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed S100A13 under transcriptional control of TEAD4 and SP1 and connected its expression to cancer cell invasion and chemoresistance.\",\n      \"evidence\": \"Luciferase promoter assays, RNAi/overexpression, cisplatin sensitivity, invasion and xenograft assays across OSCC, thyroid, lung and osteosarcoma models\",\n      \"pmids\": [\"34358353\", \"27008379\", \"18061437\", \"41787040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cancer phenotypes depend on the secretion function or another activity unresolved\", \"SP1 axis (osteosarcoma) is single-method, Low confidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physical mechanism by which the S100A13 complex translocates folded cargo across an intact plasma membrane—and how a single module selects among FGF-1, IL-1α, and prothymosin-α—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted membrane-translocation system\", \"Cargo-selection determinants not defined\", \"Unified model linking secretion, senescence, fibrosis and cancer phenotypes absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 2, 7, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 12, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17, 19]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009609\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 7, 12, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"S100A13–FGF-1–p40 synaptotagmin-1 release complex\",\n      \"IL-1α–S100A13 heterotetramer\",\n      \"S100A13–prothymosin-α complex\"\n    ],\n    \"partners\": [\n      \"FGF1\",\n      \"SYT1\",\n      \"IL1A\",\n      \"PTMA\",\n      \"STX1A\",\n      \"AGER\",\n      \"S100A3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}