{"gene":"CFP","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2005,"finding":"Properdin (CFP) promotes the association of C3b with factor B and serves as a focal point for assembly of the alternative pathway C3 convertase (C3bBb) on a surface; surface plasmon resonance assays demonstrated that properdin binds both preformed C3bBb convertases and nascent C3b/C3b-factor B intermediates, stabilizing the convertase through a lattice of properdin:ligand interactions.","method":"Surface plasmon resonance (SPR) binding assays with purified complement proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro reconstitution with purified proteins and quantitative SPR; mechanistic model supported by multiple interaction measurements","pmids":["16301317"],"is_preprint":false},{"year":1997,"finding":"Properdin (CFP) is stored in secondary (specific) granules of human neutrophils and is released upon stimulation with TNF-α, C5a, IL-8, or fMLP; properdin mRNA was detected in peripheral blood granulocytes, and subcellular fractionation by Percoll density gradients with Western blot confirmed secondary granule localization, establishing neutrophils as a local secretory source of properdin.","method":"Subcellular fractionation (Percoll density gradients), Western blotting, flow cytometry, RT-PCR","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, Western blot, flow cytometry, mRNA); finding replicated in subsequent studies","pmids":["9127010"],"is_preprint":false},{"year":2008,"finding":"Properdin (CFP) binds to early apoptotic T cells via glycosaminoglycan chains of surface proteoglycans, initiates alternative pathway complement activation leading to C3b opsonization, and promotes phagocyte uptake of apoptotic cells both complement-dependently and independently; properdin released from activated neutrophils was particularly effective at this recognition.","method":"Flow cytometry, complement deposition assays, phagocytosis assays, blocking with heparin/GAG competitors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays with specific inhibition controls; replicated in independent study (PMID:18490764)","pmids":["18579773"],"is_preprint":false},{"year":2008,"finding":"Properdin (CFP) binds predominantly to late apoptotic and necrotic cells (not early apoptotic cells) independently of C3b, serving as a direct pattern-recognition initiator of alternative pathway complement activation on dying cells; properdin was found to strongly interact with exposed DNA on late-stage dying cells.","method":"Flow cytometry, complement deposition assays, DNA-binding assays, C3b-independent binding assays using properdin-depleted serum reconstitution","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods demonstrating C3b-independent binding; mechanistically distinct from PMID:18579773 finding, adds novel mode","pmids":["18490764"],"is_preprint":false},{"year":2013,"finding":"Electron microscopy of properdin oligomers revealed that the N- and C-terminal ends of adjacent monomers form a 'curly vertex' that cross-links the AP C3 convertase by interacting simultaneously with the C345C and vWA domains of C3b and Bb respectively; properdin binding also induces a large displacement of the TED and CUB domains of C3b, impairing inactivation by regulatory proteins and facilitating recruitment of fluid-phase C3 convertase to cell surfaces.","method":"Electron microscopy, structural analysis of properdin oligomers bound to C3bBb convertase","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct structural determination by EM with functional implications for convertase stabilization mechanism","pmids":["23901101"],"is_preprint":false},{"year":2017,"finding":"Complement factor properdin (CFP) is a direct ligand for the natural killer cell-activating receptor NKp46; this interaction was shown to be functionally required for group 1 ILC/NK cell-mediated defense against Neisseria meningitidis infection in mice, revealing a direct molecular cross-talk between the complement alternative pathway and innate lymphoid cell activation.","method":"Binding assays, NKp46-deficient and CFP-deficient mouse infection models, in vivo survival experiments, receptor-ligand interaction studies","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated and functionally validated in vivo with genetic knockout models; independently significant finding","pmids":["28480349"],"is_preprint":false},{"year":2000,"finding":"Properdin (CFP) is extensively C-mannosylated: of 20 tryptophans in the protein (17 in WXXW motifs across six thrombospondin type 1 repeats), 14 were found to be 100% C-mannosylated as determined by mass spectrometry and Edman degradation, making properdin one of the most extensively C-mannosylated proteins known.","method":"Mass spectrometry, Edman degradation sequencing of purified properdin peptides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical characterization of post-translational modification by MS and Edman sequencing on purified protein","pmids":["10878002"],"is_preprint":false},{"year":2008,"finding":"Properdin (CFP) binds dose-dependently to proximal tubular epithelial cells (PTECs) but not endothelial cells, and serves as the critical focal point for alternative pathway complement activation on tubular cells; complement deposition and C5b-9 generation were virtually absent with properdin-deficient serum and fully restored by pre-incubating PTECs with properdin before adding properdin-depleted serum.","method":"In vitro binding assays, complement deposition assays with normal vs. properdin-deficient serum, immunohistochemistry of kidney biopsies","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 — functional reconstitution with properdin-deficient serum and add-back experiment; complemented by in vivo histology","pmids":["18753294"],"is_preprint":false},{"year":2013,"finding":"Physiological forms of human properdin (CFP) bind directly to activated platelets independently of C3, and recruit C3b or C3(H2O) to form C3b,Bb or a novel cell-bound C3 convertase [C3(H2O),Bb] on the platelet surface, representing a new mode of alternative pathway initiation; neutrophil-released properdin was also shown to bind activated platelets.","method":"Flow cytometry, complement deposition assays on activated platelets, properdin-deficient serum reconstitution, inhibition by anti-properdin antibodies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays with specific antibody inhibition and reconstitution controls demonstrating novel C3(H2O)-dependent convertase assembly","pmids":["23677468"],"is_preprint":false},{"year":1995,"finding":"Human complement factor properdin (CFP) binds to HIV-1 envelope glycoprotein gp41, as shown by ELISA with recombinant soluble gp41 and with gp41-gp120 complex expressed on Schneider-2 cells; factor H also bound gp41, and the binding was attributed to sequence homology between gp41 and human C3.","method":"ELISA with recombinant proteins, binding assays on stably transfected cells expressing gp41-gp120","journal":"AIDS","confidence":"Medium","confidence_rationale":"Tier 3 — single-lab binding assay; mechanistic follow-up limited to sequence homology analysis","pmids":["7893437"],"is_preprint":false},{"year":2019,"finding":"Complement factor properdin (CFP) exhibits tumor-suppressive activity in breast cancer cells: overexpression of CFP induced upregulation of the pro-apoptotic transcription factor DDIT3 (associated with ER-stress response) via TES, inhibiting MCF7 cell growth in vitro and in vivo; this represents a novel intracellular/paracrine role for CFP beyond its canonical complement function.","method":"Overexpression screening in MCF7 cell panel, in vitro cell growth assays, in vivo xenograft models, gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional phenotype with pathway placement (TES/DDIT3), but single-lab study; mechanism of how secreted properdin induces intracellular DDIT3 not fully resolved","pmids":["30755730"],"is_preprint":false},{"year":1982,"finding":"Properdin (CFP) deficiency in a family was associated with severely impaired alternative pathway functions (activation of C3 by inulin/zymosan, lysis of guinea-pig erythrocytes, opsonization of endotoxin-coated particles) while immune hemolysis via the classical pathway remained normal, establishing properdin as specifically required for alternative pathway complement activation in vivo.","method":"Hemolytic assays, opsonization assays, alternative pathway activation assays in properdin-deficient patient serum","journal":"Clinical and experimental immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays in naturally deficient human serum; classic genetic epistasis establishing pathway specificity; widely replicated","pmids":["7151327"],"is_preprint":false}],"current_model":"Complement factor properdin (CFP) is the only known positive regulator of the alternative pathway of complement, functioning by binding C3b on target surfaces to serve as a focal point for assembly and stabilization of the C3bBb convertase (via molecular cross-linking of Bb's vWA domain and C3b's C345C domain with concurrent TED/CUB domain displacement that impairs regulatory protein access); properdin is stored in neutrophil secondary granules and released upon activation, binds apoptotic/necrotic cells directly via glycosaminoglycans and exposed DNA to initiate complement independently of pre-existing C3b, activates complement on tubular epithelial cells and platelets through novel C3(H2O)-dependent convertase assembly, is extensively C-mannosylated on thrombospondin type 1 repeats, directly engages the NK cell receptor NKp46 to bridge complement and innate lymphoid cell immunity, and exhibits a tumor-suppressive function in breast cancer via TES-mediated DDIT3 upregulation."},"narrative":{"teleology":[{"year":1982,"claim":"Properdin deficiency in a human family established that CFP is specifically and non-redundantly required for alternative pathway complement activation, resolving whether the alternative pathway could function without properdin.","evidence":"Hemolytic, opsonization, and alternative pathway activation assays in naturally properdin-deficient patient serum","pmids":["7151327"],"confidence":"High","gaps":["Molecular mechanism of convertase stabilization unknown at this point","Whether properdin has functions beyond convertase stabilization not addressed"]},{"year":1997,"claim":"Demonstration that properdin is stored in neutrophil secondary granules and released by inflammatory mediators identified a local, regulatable secretory source, answering how properdin reaches sites of infection.","evidence":"Percoll density gradient fractionation, Western blot, flow cytometry, and RT-PCR in human neutrophils","pmids":["9127010"],"confidence":"High","gaps":["What surface ligands properdin recognizes on target cells unknown","Whether other cell types contribute significant properdin secretion not determined"]},{"year":2000,"claim":"Mass spectrometric characterization revealed that 14 of 17 WXXW-motif tryptophans in properdin's thrombospondin type 1 repeats are fully C-mannosylated, establishing CFP as one of the most extensively C-mannosylated human proteins and raising questions about how this modification affects folding or function.","evidence":"Mass spectrometry and Edman degradation of purified properdin peptides","pmids":["10878002"],"confidence":"High","gaps":["Functional consequences of C-mannosylation for properdin activity or oligomerization not determined","Whether C-mannosylation is required for secretion or ligand binding unknown"]},{"year":2005,"claim":"Quantitative SPR binding studies showed that properdin binds both preformed C3bBb convertases and nascent C3b/C3b-factor B intermediates, establishing that properdin serves as a platform for de novo convertase assembly rather than merely stabilizing preformed complexes.","evidence":"Surface plasmon resonance with purified complement proteins","pmids":["16301317"],"confidence":"High","gaps":["Structural basis of how properdin contacts both C3b and Bb simultaneously not resolved","Whether properdin-directed assembly occurs on physiological surfaces not shown"]},{"year":2008,"claim":"Three independent studies demonstrated that properdin binds apoptotic/necrotic cells (via glycosaminoglycans and exposed DNA) and renal tubular epithelial cells independently of C3b, redefining properdin as a direct pattern-recognition molecule capable of initiating complement activation on target surfaces.","evidence":"Flow cytometry, complement deposition assays, GAG-competition experiments, properdin-deficient serum reconstitution, and kidney biopsy immunohistochemistry","pmids":["18579773","18490764","18753294"],"confidence":"High","gaps":["Identity of the specific surface receptor/proteoglycan on tubular epithelial cells not determined","Relative in vivo contributions of C3b-dependent vs. C3b-independent properdin binding unclear"]},{"year":2013,"claim":"Electron microscopy of properdin–C3bBb complexes revealed that oligomeric properdin vertices simultaneously contact the C345C domain of C3b and the vWA domain of Bb, while displacing the TED/CUB domains to impair regulatory cofactor access — providing the first structural mechanism for convertase stabilization. Concurrently, properdin was shown to recruit C3(H2O) to activated platelets to assemble a novel cell-bound C3(H2O),Bb convertase.","evidence":"Electron microscopy of properdin–convertase complexes; flow cytometry and complement deposition assays on activated platelets with properdin-deficient serum reconstitution","pmids":["23901101","23677468"],"confidence":"High","gaps":["Atomic-resolution structure of the properdin–convertase interface not available","Physiological significance of the C3(H2O),Bb convertase on platelets in thromboinflammation not established in vivo"]},{"year":2017,"claim":"Identification of properdin as a direct ligand for the NK cell receptor NKp46 revealed a complement-independent role for CFP in innate lymphoid cell activation, bridging humoral and cellular innate immunity during bacterial infection.","evidence":"Binding assays and in vivo survival experiments in NKp46-deficient and CFP-deficient mouse Neisseria meningitidis infection models","pmids":["28480349"],"confidence":"High","gaps":["Binding interface between properdin and NKp46 not structurally defined","Whether properdin–NKp46 interaction is relevant to viral or tumor contexts unknown"]},{"year":2019,"claim":"Overexpression studies revealed a tumor-suppressive role for CFP in breast cancer through TES-mediated upregulation of the ER-stress factor DDIT3, suggesting a complement-independent intracellular or paracrine function.","evidence":"Overexpression in MCF7 cells, in vitro growth assays, in vivo xenograft models, gene expression analysis","pmids":["30755730"],"confidence":"Medium","gaps":["Mechanism by which a secreted complement protein induces intracellular DDIT3 via TES not resolved","Not independently replicated in other breast cancer models or cell lines","Whether the effect is direct (intracrine) or paracrine remains unclear"]},{"year":null,"claim":"Key open questions include the atomic-resolution structure of the properdin–C3bBb complex, the functional impact of extensive C-mannosylation on properdin activity, and whether the NKp46-binding and tumor-suppressive roles reflect independent or interconnected biological functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution crystal or cryo-EM structure of properdin in complex with C3bBb","Functional consequence of C-mannosylation on properdin folding, secretion, or ligand binding untested","Relationship between NKp46-mediated NK activation and complement effector functions not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,8,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3,7,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,4,5,7,8,11]}],"complexes":["C3bBb alternative pathway C3 convertase"],"partners":["C3B","CFB","NKP46"],"other_free_text":[]},"mechanistic_narrative":"Properdin (CFP) is the sole positive regulator of the alternative complement pathway, functioning both as a stabilizer of the C3bBb convertase and as a pattern-recognition molecule that initiates complement activation on target surfaces. Properdin cross-links the C345C domain of C3b and the vWA domain of Bb through its oligomeric vertices, displacing the TED/CUB domains to impair regulatory protein access and thereby prolonging convertase half-life [PMID:23901101, PMID:16301317]. Stored in neutrophil secondary granules and released upon inflammatory stimulation, properdin binds apoptotic/necrotic cells via glycosaminoglycans and exposed DNA, activated platelets, and renal tubular epithelial cells independently of pre-existing C3b, recruiting C3b or C3(H2O) to assemble convertases de novo [PMID:9127010, PMID:18579773, PMID:18490764, PMID:23677468, PMID:18753294]. Beyond complement, properdin directly engages the NK cell-activating receptor NKp46 to bridge alternative pathway activation with innate lymphoid cell defense against Neisseria meningitidis [PMID:28480349], and inherited properdin deficiency abolishes alternative pathway function while leaving the classical pathway intact [PMID:7151327]."},"prefetch_data":{"uniprot":{"accession":"P27918","full_name":"Properdin","aliases":["Complement factor P"],"length_aa":469,"mass_kda":51.3,"function":"A positive regulator of the alternate pathway (AP) of complement (PubMed:16301317, PubMed:20382442, PubMed:28264884, PubMed:9748277). It binds to and stabilizes the C3- and C5-convertase enzyme complexes (PubMed:16301317, PubMed:20382442, PubMed:28264884, PubMed:9748277). Inhibits CFI-CFH mediated degradation of Complement C3 beta chain (C3b) (PubMed:31507604)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P27918/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFP","total_profiled":1310},"omim":[{"mim_id":"617579","title":"CLAUDIN 10; CLDN10","url":"https://www.omim.org/entry/617579"},{"mim_id":"313440","title":"SYNAPSIN I; SYN1","url":"https://www.omim.org/entry/313440"},{"mim_id":"312060","title":"PROPERDIN DEFICIENCY, X-LINKED; CFPD","url":"https://www.omim.org/entry/312060"},{"mim_id":"300383","title":"COMPLEMENT FACTOR PROPERDIN; CFP","url":"https://www.omim.org/entry/300383"},{"mim_id":"161400","title":"NARCOLEPSY 1; NRCLP1","url":"https://www.omim.org/entry/161400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":79.3},{"tissue":"lymphoid tissue","ntpm":50.0}],"url":"https://www.proteinatlas.org/search/CFP"},"hgnc":{"alias_symbol":[],"prev_symbol":["PFC"]},"alphafold":{"accession":"P27918","domains":[{"cath_id":"-","chopping":"316-453","consensus_level":"medium","plddt":91.1715,"start":316,"end":453}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27918","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27918-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27918-F1-predicted_aligned_error_v6.png","plddt_mean":83.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFP","jax_strain_url":"https://www.jax.org/strain/search?query=CFP"},"sequence":{"accession":"P27918","fasta_url":"https://rest.uniprot.org/uniprotkb/P27918.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27918/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27918"}},"corpus_meta":[{"pmid":"9846755","id":"PMC_9846755","title":"A Mycobacterium tuberculosis operon encoding ESAT-6 and a novel low-molecular-mass culture filtrate protein (CFP-10).","date":"1998","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9846755","citation_count":380,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11940590","id":"PMC_11940590","title":"Conclusive evidence that the major T-cell antigens of the Mycobacterium tuberculosis complex ESAT-6 and CFP-10 form a tight, 1:1 complex and characterization of the structural properties of ESAT-6, CFP-10, and the ESAT-6*CFP-10 complex. 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complement.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16301317","citation_count":169,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19322201","id":"PMC_19322201","title":"Ubiquitin-mediated proteolysis of HuR by heat shock.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19322201","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18579773","id":"PMC_18579773","title":"The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18579773","citation_count":132,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7151327","id":"PMC_7151327","title":"Properdin deficiency in a family with fulminant meningococcal infections.","date":"1982","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7151327","citation_count":127,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9127010","id":"PMC_9127010","title":"Properdin, a positive regulator of complement activation, is released from secondary granules of stimulated peripheral blood neutrophils.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9127010","citation_count":120,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18490764","id":"PMC_18490764","title":"Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative 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binding.","date":"2008","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18753294","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23677468","id":"PMC_23677468","title":"Identification of a novel mode of complement activation on stimulated platelets mediated by properdin and C3(H2O).","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23677468","citation_count":73,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10878002","id":"PMC_10878002","title":"Properdin, the positive regulator of complement, is highly C-mannosylated.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10878002","citation_count":70,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23901101","id":"PMC_23901101","title":"Structural basis for the stabilization of the complement alternative pathway C3 convertase by properdin.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23901101","citation_count":68,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50599,"output_tokens":3018,"usd":0.098533},"stage2":{"model":"claude-opus-4-6","input_tokens":6416,"output_tokens":2335,"usd":0.135683},"total_usd":0.498164,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":63710,"output_tokens":3998,"usd":0.12555},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6623,"output_tokens":2366,"usd":0.138398}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"ESAT-6 and CFP-10 (Mycobacterium tuberculosis) form a tight 1:1 heterodimeric complex in which both proteins adopt a fully folded, predominantly helical structure; individually, ESAT-6 exists in a molten-globule-like state and CFP-10 is an unstructured random coil.\",\n      \"method\": \"Fluorescence spectroscopy, circular dichroism, and NMR spectroscopy with overexpressed recombinant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biophysical methods in a single rigorous study; foundational structural characterization replicated by subsequent work\",\n      \"pmids\": [\"11940590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The solution structure of the CFP-10·ESAT-6 complex was determined; a long flexible C-terminal arm of CFP-10 is essential for binding to the surface of macrophage and monocyte cells, indicating a key signalling role for the complex at host cell surfaces.\",\n      \"method\": \"NMR solution structure determination combined with fluorescence microscopy binding assay; functional mutagenesis of CFP-10 C-terminus\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus functional cell-binding assay with mechanistic follow-up; replicated the 1:1 complex finding with added structural detail\",\n      \"pmids\": [\"15973432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ESAT-6 dissociates from its putative chaperone CFP-10 under acidic conditions (mimicking the phagosome environment) and the liberated ESAT-6 directly destabilizes and lyses lipid bilayers, whereas CFP-10 alone does not lyse membranes; the intact ESAT-6·CFP-10 complex does not associate strongly with membranes.\",\n      \"method\": \"Flotation gradient centrifugation with liposomal preparations (DMPC/DMPG/cholesterol), cryo-electron microscopy, pH-shift dissociation assay\",\n      \"journal\": \"Journal of bacteriology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted membrane-lysis assay with multiple lipid compositions, cryo-EM visualization, and pH-dependent dissociation experiment\",\n      \"pmids\": [\"17557817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ESAT-6·CFP-10 complex formation confers thermodynamic and biochemical stability: the heterodimer has an association constant of ~2×10^7 M−1 (ΔG = −9.95 kcal/mol), its thermal unfolding is fully reversible (Tm = 53.4 °C), and complex formation protects ESAT-6 and the N-terminal region of CFP-10 from trypsin proteolysis while leaving the functionally important flexible C-terminus of CFP-10 accessible.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), circular dichroism thermal unfolding, limited trypsin proteolysis, phospholipid membrane interaction assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative thermodynamic parameters from ITC plus multiple orthogonal stability assays\",\n      \"pmids\": [\"16689931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The ESX-1 secretion system (specifically the ATPase component orthologous to Rv3871) is required for secretion of ESAT-6 and CFP-10, and this secretion system prevents phagosome maturation and acidification in macrophages, enabling intracellular bacterial survival.\",\n      \"method\": \"Genetic mutant isolation and complementation in M. marinum, confocal and electron microscopy with LAMP-1, fluid-phase markers, and LysoTracker Red in infected J774 macrophages\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function mutant with defined cellular phenotype (phagosome maturation), complementation, and multiple imaging modalities\",\n      \"pmids\": [\"16922861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A novel ESX-1-secreted protein Mh3881c (Rv3881c homolog) is co-secreted with CFP-10 and ESAT-6 in a co-dependent manner; the C-terminal cleavage product of Mh3881c interacts with ESAT-6 and is required for ESX-1-dependent phagosome maturation inhibition and intracellular growth in macrophages.\",\n      \"method\": \"Secretome analysis by mass spectrometry, co-immunoprecipitation, genetic complementation, macrophage infection assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based interactome plus Co-IP, genetic complementation in two species, and functional cellular readout\",\n      \"pmids\": [\"17908204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CFP-10 and ESAT-6 individually and as a complex inhibit LPS-induced NF-κB p65 DNA-binding activity and NF-κB-dependent reporter gene expression in macrophages by downregulating reactive oxygen species (ROS) production.\",\n      \"method\": \"ROS measurement in RAW264.7 cells, NF-κB p65 EMSA, chloramphenicol acetyltransferase reporter assay, N-acetyl cysteine ROS scavenger control\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in a single lab; mechanistic link (ROS→NF-κB) established with chemical rescue\",\n      \"pmids\": [\"17909563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The ESAT-6/CFP-10 fusion protein expressed ectopically in macrophages inhibits autophagosome formation and decreases expression of autophagy-related gene atg8, resulting in increased intracellular M. tuberculosis survival.\",\n      \"method\": \"Ectopic expression in macrophages, fluorescence microscopy (autophagosome quantification), qRT-PCR for ATG genes, bacterial viability assay, rapamycin co-treatment\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss/gain-of-function with defined autophagy phenotype and gene-expression readout; single lab\",\n      \"pmids\": [\"21740189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CFP-10 (but not ESAT-6) in the ESAT-6:CFP-10 complex specifically activates human neutrophils through a pertussis toxin-sensitive G-protein-coupled receptor, triggering intracellular Ca²⁺ release, NADPH-oxidase-dependent superoxide production, and neutrophil chemotaxis; monocytes and lymphocytes do not respond.\",\n      \"method\": \"Ca²⁺ flux assay, pertussis toxin inhibition, NADPH-oxidase activity assay, chemotaxis assay; recombinant individual proteins and complex tested on isolated human leukocyte populations\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with pharmacological receptor identification (pertussis toxin), cell-type specificity controls, and separation of CFP-10 from ESAT-6 contribution\",\n      \"pmids\": [\"25332123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CFP-10/ESAT-6 family proteins form tight 1:1 complexes strictly between genome-paired partners; Rv0287/Rv0288 and Rv3019c/Rv3020c also form inter-pair complexes with each other but do not bind the more distantly related CFP-10/ESAT-6 pair, establishing partner-specificity rules governing complex formation.\",\n      \"method\": \"Yeast two-hybrid analysis and biochemical co-purification assays\",\n      \"journal\": \"FEMS microbiology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal methods (Y2H and biochemical), but single lab\",\n      \"pmids\": [\"15336430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EspA residues W55 and G57 (W-X-G motif) are required for ESAT-6 and CFP-10 secretion and M. tuberculosis virulence, but certain other EspA mutations (F5R, K41A) block in vitro ESAT-6/CFP-10 secretion without attenuating virulence, demonstrating that in vitro secretion blockage and attenuation are not always coupled.\",\n      \"method\": \"Site-directed mutagenesis of EspA, in vitro secretion assay, cellular infection models, mouse acute infection model\",\n      \"journal\": \"Journal of bacteriology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis with in vitro and in vivo functional readouts; single lab but multiple alleles tested\",\n      \"pmids\": [\"24078612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Complement factor properdin (CFP) suppresses breast cancer cell growth by inducing intracellular upregulation of the pro-apoptotic transcription factor DDIT3, associated with endoplasmic reticulum stress response, both in vitro and in vivo.\",\n      \"method\": \"Overexpression of wild-type vs. mutant CFP in MCF7 cells, cell growth assays, xenograft mouse models; DDIT3 protein-level measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional assays with mechanistic pathway identification (CFP→DDIT3→apoptosis); single lab\",\n      \"pmids\": [\"30755730\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"In the context of Mycobacterium tuberculosis, the secreted CFP-10 protein functions primarily as a chaperone that forms a tight 1:1 heterodimer with ESAT-6, stabilizing both proteins and suppressing ESAT-6's membrane-lytic activity until acidic phagosomal conditions trigger complex dissociation; free ESAT-6 then lyses membranes to prevent phagolysosomal fusion, while CFP-10 itself directly activates human neutrophils via a pertussis toxin-sensitive GPCR to trigger Ca²⁺ flux, superoxide production, and chemotaxis; additionally, for the human complement factor properdin (CFP), a tumor-suppressive role has been identified in breast cancer cells through intracellular induction of the ER-stress transcription factor DDIT3.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI need to classify each paper for the gene CFP, which is the human gene encoding **complement factor properdin** (CFP, also known as properdin).\n\n**Classification:**\n\n- Papers about Mycobacterium tuberculosis CFP-10 (culture filtrate protein 10) → EXCLUDE (alias collision - \"CFP-10\" is not human CFP/properdin)\n- Papers about cyan fluorescent protein (CFP used in FRET) → EXCLUDE (alias collision)\n- Papers about PFC (prefrontal cortex) → EXCLUDE (abbreviation collision)\n- Papers about C. elegans CFP-1 (CXXC zinc finger) → EXCLUDE (alias collision, different protein)\n- Papers about Neurospora crassa cfp promoter → EXCLUDE (symbol collision, fungal gene)\n- Papers about Cercospora CFP (cercosporin facilitator protein) → EXCLUDE (symbol collision, fungal gene)\n- Papers about Cladonia furcata CFP-2 (polysaccharide) → EXCLUDE (not a protein-coding gene product)\n- Papers about human complement factor properdin (CFP) → KEEP\n\n**KEPT papers:**\n- PMID:16301317 — Properdin role in assembly of alternative pathway C3 convertases\n- PMID:18579773 — Properdin binds apoptotic T cells, promotes complement activation\n- PMID:7151327 — Properdin deficiency and meningococcal infections\n- PMID:9127010 — Properdin stored in neutrophil secondary granules\n- PMID:18490764 — Properdin binds late apoptotic/necrotic cells independently of C3b\n- PMID:28480349 — CFP is a ligand for NKp46\n- PMID:7893437 — Complement proteins interact with HIV-1 gp41/gp120\n- PMID:12096136 — C-mannosylation and O-fucosylation of TSRs\n- PMID:10878002 — Properdin is highly C-mannosylated\n- PMID:23901101 — Structural basis for stabilization of AP C3 convertase by properdin\n- PMID:18753294 — Complement activation by tubular cells mediated by properdin binding\n- PMID:23677468 — Novel mode of complement activation on platelets via properdin\n- PMID:22518841 — CFHR4 assembles AP C3 convertase via C3b interaction (about CFHR4, not CFP directly — borderline; mentions properdin but focuses on CFHR4) → EXCLUDE\n- PMID:28086806 — ARMS2 recruits properdin for complement activation (about ARMS2, not CFP directly) → EXCLUDE for primary focus, but properdin binding is mechanistic → KEEP for CFP's role\n- PMID:30755730 — CFP suppresses breast cancer cell growth via TES/DDIT3 → KEEP (canonical human CFP/properdin, novel intracellular role described)\n- PMID:15199963 — Lectin-complement pathway review (mentions properdin but not mechanistic for CFP specifically) → weak, but mentions alternative pathway\n- PMID:19913121 — Gene-centric lipid associations (genome paper, no mechanistic CFP finding) → EXCLUDE\n- Interactome papers (PMID:28514442, 32296183, 33961781) → large-scale MS studies identifying CFP interactions → Low confidence interactome data, include if mechanistic\n- PMID:12477932, 14702039, 15489334, 16344560, 15772651 — genomic/cDNA sequencing papers → EXCLUDE (no mechanistic findings)\n- PMID:19322201 — HuR ubiquitination → EXCLUDE (not CFP)\n- PMID:7142121 — IgG Fc fragments → EXCLUDE (not CFP)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Properdin (CFP) promotes the association of C3b with factor B and serves as a focal point for assembly of the alternative pathway C3 convertase (C3bBb) on a surface; surface plasmon resonance assays demonstrated that properdin binds both preformed C3bBb convertases and nascent C3b/C3b-factor B intermediates, stabilizing the convertase through a lattice of properdin:ligand interactions.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding assays with purified complement proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro reconstitution with purified proteins and quantitative SPR; mechanistic model supported by multiple interaction measurements\",\n      \"pmids\": [\"16301317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Properdin (CFP) is stored in secondary (specific) granules of human neutrophils and is released upon stimulation with TNF-α, C5a, IL-8, or fMLP; properdin mRNA was detected in peripheral blood granulocytes, and subcellular fractionation by Percoll density gradients with Western blot confirmed secondary granule localization, establishing neutrophils as a local secretory source of properdin.\",\n      \"method\": \"Subcellular fractionation (Percoll density gradients), Western blotting, flow cytometry, RT-PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, Western blot, flow cytometry, mRNA); finding replicated in subsequent studies\",\n      \"pmids\": [\"9127010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Properdin (CFP) binds to early apoptotic T cells via glycosaminoglycan chains of surface proteoglycans, initiates alternative pathway complement activation leading to C3b opsonization, and promotes phagocyte uptake of apoptotic cells both complement-dependently and independently; properdin released from activated neutrophils was particularly effective at this recognition.\",\n      \"method\": \"Flow cytometry, complement deposition assays, phagocytosis assays, blocking with heparin/GAG competitors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with specific inhibition controls; replicated in independent study (PMID:18490764)\",\n      \"pmids\": [\"18579773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Properdin (CFP) binds predominantly to late apoptotic and necrotic cells (not early apoptotic cells) independently of C3b, serving as a direct pattern-recognition initiator of alternative pathway complement activation on dying cells; properdin was found to strongly interact with exposed DNA on late-stage dying cells.\",\n      \"method\": \"Flow cytometry, complement deposition assays, DNA-binding assays, C3b-independent binding assays using properdin-depleted serum reconstitution\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods demonstrating C3b-independent binding; mechanistically distinct from PMID:18579773 finding, adds novel mode\",\n      \"pmids\": [\"18490764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Electron microscopy of properdin oligomers revealed that the N- and C-terminal ends of adjacent monomers form a 'curly vertex' that cross-links the AP C3 convertase by interacting simultaneously with the C345C and vWA domains of C3b and Bb respectively; properdin binding also induces a large displacement of the TED and CUB domains of C3b, impairing inactivation by regulatory proteins and facilitating recruitment of fluid-phase C3 convertase to cell surfaces.\",\n      \"method\": \"Electron microscopy, structural analysis of properdin oligomers bound to C3bBb convertase\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural determination by EM with functional implications for convertase stabilization mechanism\",\n      \"pmids\": [\"23901101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Complement factor properdin (CFP) is a direct ligand for the natural killer cell-activating receptor NKp46; this interaction was shown to be functionally required for group 1 ILC/NK cell-mediated defense against Neisseria meningitidis infection in mice, revealing a direct molecular cross-talk between the complement alternative pathway and innate lymphoid cell activation.\",\n      \"method\": \"Binding assays, NKp46-deficient and CFP-deficient mouse infection models, in vivo survival experiments, receptor-ligand interaction studies\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated and functionally validated in vivo with genetic knockout models; independently significant finding\",\n      \"pmids\": [\"28480349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Properdin (CFP) is extensively C-mannosylated: of 20 tryptophans in the protein (17 in WXXW motifs across six thrombospondin type 1 repeats), 14 were found to be 100% C-mannosylated as determined by mass spectrometry and Edman degradation, making properdin one of the most extensively C-mannosylated proteins known.\",\n      \"method\": \"Mass spectrometry, Edman degradation sequencing of purified properdin peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization of post-translational modification by MS and Edman sequencing on purified protein\",\n      \"pmids\": [\"10878002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Properdin (CFP) binds dose-dependently to proximal tubular epithelial cells (PTECs) but not endothelial cells, and serves as the critical focal point for alternative pathway complement activation on tubular cells; complement deposition and C5b-9 generation were virtually absent with properdin-deficient serum and fully restored by pre-incubating PTECs with properdin before adding properdin-depleted serum.\",\n      \"method\": \"In vitro binding assays, complement deposition assays with normal vs. properdin-deficient serum, immunohistochemistry of kidney biopsies\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution with properdin-deficient serum and add-back experiment; complemented by in vivo histology\",\n      \"pmids\": [\"18753294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Physiological forms of human properdin (CFP) bind directly to activated platelets independently of C3, and recruit C3b or C3(H2O) to form C3b,Bb or a novel cell-bound C3 convertase [C3(H2O),Bb] on the platelet surface, representing a new mode of alternative pathway initiation; neutrophil-released properdin was also shown to bind activated platelets.\",\n      \"method\": \"Flow cytometry, complement deposition assays on activated platelets, properdin-deficient serum reconstitution, inhibition by anti-properdin antibodies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with specific antibody inhibition and reconstitution controls demonstrating novel C3(H2O)-dependent convertase assembly\",\n      \"pmids\": [\"23677468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human complement factor properdin (CFP) binds to HIV-1 envelope glycoprotein gp41, as shown by ELISA with recombinant soluble gp41 and with gp41-gp120 complex expressed on Schneider-2 cells; factor H also bound gp41, and the binding was attributed to sequence homology between gp41 and human C3.\",\n      \"method\": \"ELISA with recombinant proteins, binding assays on stably transfected cells expressing gp41-gp120\",\n      \"journal\": \"AIDS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-lab binding assay; mechanistic follow-up limited to sequence homology analysis\",\n      \"pmids\": [\"7893437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Complement factor properdin (CFP) exhibits tumor-suppressive activity in breast cancer cells: overexpression of CFP induced upregulation of the pro-apoptotic transcription factor DDIT3 (associated with ER-stress response) via TES, inhibiting MCF7 cell growth in vitro and in vivo; this represents a novel intracellular/paracrine role for CFP beyond its canonical complement function.\",\n      \"method\": \"Overexpression screening in MCF7 cell panel, in vitro cell growth assays, in vivo xenograft models, gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional phenotype with pathway placement (TES/DDIT3), but single-lab study; mechanism of how secreted properdin induces intracellular DDIT3 not fully resolved\",\n      \"pmids\": [\"30755730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1982,\n      \"finding\": \"Properdin (CFP) deficiency in a family was associated with severely impaired alternative pathway functions (activation of C3 by inulin/zymosan, lysis of guinea-pig erythrocytes, opsonization of endotoxin-coated particles) while immune hemolysis via the classical pathway remained normal, establishing properdin as specifically required for alternative pathway complement activation in vivo.\",\n      \"method\": \"Hemolytic assays, opsonization assays, alternative pathway activation assays in properdin-deficient patient serum\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in naturally deficient human serum; classic genetic epistasis establishing pathway specificity; widely replicated\",\n      \"pmids\": [\"7151327\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Complement factor properdin (CFP) is the only known positive regulator of the alternative pathway of complement, functioning by binding C3b on target surfaces to serve as a focal point for assembly and stabilization of the C3bBb convertase (via molecular cross-linking of Bb's vWA domain and C3b's C345C domain with concurrent TED/CUB domain displacement that impairs regulatory protein access); properdin is stored in neutrophil secondary granules and released upon activation, binds apoptotic/necrotic cells directly via glycosaminoglycans and exposed DNA to initiate complement independently of pre-existing C3b, activates complement on tubular epithelial cells and platelets through novel C3(H2O)-dependent convertase assembly, is extensively C-mannosylated on thrombospondin type 1 repeats, directly engages the NK cell receptor NKp46 to bridge complement and innate lymphoid cell immunity, and exhibits a tumor-suppressive function in breast cancer via TES-mediated DDIT3 upregulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CFP (complement factor properdin) is a positive regulator of the alternative complement pathway that also exerts an intracellular tumor-suppressive function: ectopic expression in breast cancer cells induces the ER-stress transcription factor DDIT3, leading to growth suppression both in vitro and in xenograft models [PMID:30755730]. Note: the majority of the discovery timeline for the gene symbol 'CFP' in this dataset pertains to the unrelated Mycobacterium tuberculosis secreted protein CFP-10 (EsxB), which forms a tight 1:1 heterodimer with ESAT-6 that stabilizes both partners, is co-secreted via the ESX-1 system, and whose flexible C-terminal arm mediates host-cell binding [PMID:11940590, PMID:15973432, PMID:16689931]. Upon acidification in the phagosome the complex dissociates, releasing ESAT-6 to lyse membranes and block phagosome maturation, while CFP-10 independently activates human neutrophils through a pertussis toxin–sensitive GPCR to trigger Ca²⁺ flux, superoxide production, and chemotaxis [PMID:17557817, PMID:16922861, PMID:25332123].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Determining the biophysical state of individual versus paired ESAT-6 and CFP-10 established that the heterodimer is the functional unit: ESAT-6 alone is a molten globule and CFP-10 alone is unstructured, but together they form a stable, fully helical 1:1 complex.\",\n      \"evidence\": \"Fluorescence spectroscopy, CD, and NMR on recombinant M. tuberculosis proteins\",\n      \"pmids\": [\"11940590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure yet\", \"In vivo relevance of individual disordered states unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Partner-specificity rules were established showing that CFP-10/ESAT-6 family members pair strictly with genome-linked partners, explaining why cross-family complex formation does not occur.\",\n      \"evidence\": \"Yeast two-hybrid and co-purification across multiple ESX family pairs\",\n      \"pmids\": [\"15336430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for specificity not defined\", \"Only a subset of ESX pairs tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The NMR solution structure of the CFP-10·ESAT-6 complex revealed a flexible C-terminal arm on CFP-10 that is essential for binding to macrophage surfaces, identifying CFP-10 as the host-interaction moiety.\",\n      \"evidence\": \"NMR structure plus fluorescence microscopy binding assays and C-terminal mutagenesis\",\n      \"pmids\": [\"15973432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host receptor identity unknown\", \"Binding mechanism at the membrane not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Quantitative thermodynamic characterization (Kₐ ~2×10⁷ M⁻¹, reversible unfolding) confirmed tight complex formation and showed that the C-terminus of CFP-10 remains protease-accessible in the complex, reconciling stability with signalling function.\",\n      \"evidence\": \"ITC, CD thermal melts, limited trypsin proteolysis\",\n      \"pmids\": [\"16689931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational modifications in vivo not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic disruption of the ESX-1 ATPase demonstrated that the secretion system is required for ESAT-6/CFP-10 export and for preventing phagosome maturation in macrophages, linking secretion to virulence.\",\n      \"evidence\": \"Complementation of M. marinum ESX-1 mutants, LAMP-1 and LysoTracker imaging in J774 macrophages\",\n      \"pmids\": [\"16922861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role of each secreted protein in phagosome arrest not separated\", \"Host signaling pathway mediating arrest not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"pH-dependent dissociation of the complex was shown to release free ESAT-6, which directly lyses lipid bilayers, while CFP-10 and the intact complex do not, establishing a 'chaperone-then-effector' model for phagosome disruption.\",\n      \"evidence\": \"Liposome flotation assays, cryo-EM, pH-shift dissociation with recombinant proteins\",\n      \"pmids\": [\"17557817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ESAT-6 membrane insertion not resolved at molecular level\", \"Whether other ESX-1 substrates contribute to lysis in vivo unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Both CFP-10 and ESAT-6, individually and as a complex, were found to inhibit NF-κB p65 activation in macrophages by suppressing LPS-induced ROS, revealing an immunomodulatory role distinct from membrane lysis.\",\n      \"evidence\": \"ROS quantification, EMSA, CAT reporter assay in RAW264.7 macrophages with NAC rescue\",\n      \"pmids\": [\"17909563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target in the ROS pathway not identified\", \"Physiological protein concentrations in the phagosome not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expression of an ESAT-6/CFP-10 fusion in macrophages inhibited autophagosome formation and reduced atg8 expression, linking the complex to evasion of autophagic killing.\",\n      \"evidence\": \"Ectopic expression, fluorescence microscopy autophagosome counts, qRT-PCR, bacterial survival assay\",\n      \"pmids\": [\"21740189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fusion protein may not recapitulate individual protein activities\", \"Mechanism linking the complex to ATG8 transcriptional repression unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CFP-10 was identified as a neutrophil-specific activator acting through a pertussis toxin–sensitive GPCR, triggering intracellular Ca²⁺ release, NADPH-oxidase superoxide, and chemotaxis — functions not shared by ESAT-6 — establishing a direct immune-stimulatory activity for CFP-10.\",\n      \"evidence\": \"Ca²⁺ flux, pertussis toxin blockade, superoxide assay, and chemotaxis on isolated human leukocyte subsets\",\n      \"pmids\": [\"25332123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the GPCR not determined\", \"In vivo significance during infection not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"For human complement factor properdin (CFP), a tumor-suppressive role was demonstrated: intracellular CFP upregulates the ER-stress factor DDIT3, suppressing breast cancer cell growth in vitro and in xenografts.\",\n      \"evidence\": \"Overexpression of wild-type vs. mutant CFP in MCF7 cells, cell growth and xenograft assays, DDIT3 protein measurement\",\n      \"pmids\": [\"30755730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which intracellular properdin induces DDIT3 not resolved\", \"Relationship to properdin's canonical extracellular complement role unclear\", \"Not replicated in independent labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"For human properdin (CFP), the intracellular signaling mechanism connecting properdin to DDIT3 induction and ER stress remains undefined, as does whether this tumor-suppressive activity operates through or independently of complement activation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding partner or enzymatic substrate identified for intracellular properdin\", \"No structural basis for DDIT3 induction\", \"Complement-independent vs. complement-dependent mechanisms not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DDIT3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Properdin (CFP) is the sole positive regulator of the alternative complement pathway, functioning both as a stabilizer of the C3bBb convertase and as a pattern-recognition molecule that initiates complement activation on target surfaces. Properdin cross-links the C345C domain of C3b and the vWA domain of Bb through its oligomeric vertices, displacing the TED/CUB domains to impair regulatory protein access and thereby prolonging convertase half-life [PMID:23901101, PMID:16301317]. Stored in neutrophil secondary granules and released upon inflammatory stimulation, properdin binds apoptotic/necrotic cells via glycosaminoglycans and exposed DNA, activated platelets, and renal tubular epithelial cells independently of pre-existing C3b, recruiting C3b or C3(H2O) to assemble convertases de novo [PMID:9127010, PMID:18579773, PMID:18490764, PMID:23677468, PMID:18753294]. Beyond complement, properdin directly engages the NK cell-activating receptor NKp46 to bridge alternative pathway activation with innate lymphoid cell defense against Neisseria meningitidis [PMID:28480349], and inherited properdin deficiency abolishes alternative pathway function while leaving the classical pathway intact [PMID:7151327].\",\n  \"teleology\": [\n    {\n      \"year\": 1982,\n      \"claim\": \"Properdin deficiency in a human family established that CFP is specifically and non-redundantly required for alternative pathway complement activation, resolving whether the alternative pathway could function without properdin.\",\n      \"evidence\": \"Hemolytic, opsonization, and alternative pathway activation assays in naturally properdin-deficient patient serum\",\n      \"pmids\": [\"7151327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of convertase stabilization unknown at this point\",\n        \"Whether properdin has functions beyond convertase stabilization not addressed\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that properdin is stored in neutrophil secondary granules and released by inflammatory mediators identified a local, regulatable secretory source, answering how properdin reaches sites of infection.\",\n      \"evidence\": \"Percoll density gradient fractionation, Western blot, flow cytometry, and RT-PCR in human neutrophils\",\n      \"pmids\": [\"9127010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"What surface ligands properdin recognizes on target cells unknown\",\n        \"Whether other cell types contribute significant properdin secretion not determined\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mass spectrometric characterization revealed that 14 of 17 WXXW-motif tryptophans in properdin's thrombospondin type 1 repeats are fully C-mannosylated, establishing CFP as one of the most extensively C-mannosylated human proteins and raising questions about how this modification affects folding or function.\",\n      \"evidence\": \"Mass spectrometry and Edman degradation of purified properdin peptides\",\n      \"pmids\": [\"10878002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of C-mannosylation for properdin activity or oligomerization not determined\",\n        \"Whether C-mannosylation is required for secretion or ligand binding unknown\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Quantitative SPR binding studies showed that properdin binds both preformed C3bBb convertases and nascent C3b/C3b-factor B intermediates, establishing that properdin serves as a platform for de novo convertase assembly rather than merely stabilizing preformed complexes.\",\n      \"evidence\": \"Surface plasmon resonance with purified complement proteins\",\n      \"pmids\": [\"16301317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of how properdin contacts both C3b and Bb simultaneously not resolved\",\n        \"Whether properdin-directed assembly occurs on physiological surfaces not shown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Three independent studies demonstrated that properdin binds apoptotic/necrotic cells (via glycosaminoglycans and exposed DNA) and renal tubular epithelial cells independently of C3b, redefining properdin as a direct pattern-recognition molecule capable of initiating complement activation on target surfaces.\",\n      \"evidence\": \"Flow cytometry, complement deposition assays, GAG-competition experiments, properdin-deficient serum reconstitution, and kidney biopsy immunohistochemistry\",\n      \"pmids\": [\"18579773\", \"18490764\", \"18753294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the specific surface receptor/proteoglycan on tubular epithelial cells not determined\",\n        \"Relative in vivo contributions of C3b-dependent vs. C3b-independent properdin binding unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Electron microscopy of properdin–C3bBb complexes revealed that oligomeric properdin vertices simultaneously contact the C345C domain of C3b and the vWA domain of Bb, while displacing the TED/CUB domains to impair regulatory cofactor access — providing the first structural mechanism for convertase stabilization. Concurrently, properdin was shown to recruit C3(H2O) to activated platelets to assemble a novel cell-bound C3(H2O),Bb convertase.\",\n      \"evidence\": \"Electron microscopy of properdin–convertase complexes; flow cytometry and complement deposition assays on activated platelets with properdin-deficient serum reconstitution\",\n      \"pmids\": [\"23901101\", \"23677468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the properdin–convertase interface not available\",\n        \"Physiological significance of the C3(H2O),Bb convertase on platelets in thromboinflammation not established in vivo\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of properdin as a direct ligand for the NK cell receptor NKp46 revealed a complement-independent role for CFP in innate lymphoid cell activation, bridging humoral and cellular innate immunity during bacterial infection.\",\n      \"evidence\": \"Binding assays and in vivo survival experiments in NKp46-deficient and CFP-deficient mouse Neisseria meningitidis infection models\",\n      \"pmids\": [\"28480349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding interface between properdin and NKp46 not structurally defined\",\n        \"Whether properdin–NKp46 interaction is relevant to viral or tumor contexts unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Overexpression studies revealed a tumor-suppressive role for CFP in breast cancer through TES-mediated upregulation of the ER-stress factor DDIT3, suggesting a complement-independent intracellular or paracrine function.\",\n      \"evidence\": \"Overexpression in MCF7 cells, in vitro growth assays, in vivo xenograft models, gene expression analysis\",\n      \"pmids\": [\"30755730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which a secreted complement protein induces intracellular DDIT3 via TES not resolved\",\n        \"Not independently replicated in other breast cancer models or cell lines\",\n        \"Whether the effect is direct (intracrine) or paracrine remains unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the atomic-resolution structure of the properdin–C3bBb complex, the functional impact of extensive C-mannosylation on properdin activity, and whether the NKp46-binding and tumor-suppressive roles reflect independent or interconnected biological functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution crystal or cryo-EM structure of properdin in complex with C3bBb\",\n        \"Functional consequence of C-mannosylation on properdin folding, secretion, or ligand binding untested\",\n        \"Relationship between NKp46-mediated NK activation and complement effector functions not integrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 8, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3, 7, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 7, 8, 11]}\n    ],\n    \"complexes\": [\n      \"C3bBb alternative pathway C3 convertase\"\n    ],\n    \"partners\": [\n      \"C3b\",\n      \"CFB\",\n      \"NKp46\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}