{"gene":"SEZ6L","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2016,"finding":"SEZ6L is a physiological substrate of BACE1 (beta-secretase) in neurons: BACE1 cleaves SEZ6L near the membrane to release a soluble ectodomain (sSEZ6L); BACE1 inhibition increases neuronal surface levels of SEZ6L and reduces sSEZ6L in CSF of BACE1-deficient mice. Mass spectrometry mapped the BACE1 cleavage site in SEZ6L to a position close to the transmembrane domain.","method":"Cell surface biotinylation, primary neuron BACE1 inhibition, BACE1-knockout mouse CSF proteomics, antibody validation, mass spectrometric cleavage-site mapping","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro and in vivo methods, validated in primary neurons and BACE1-KO mice, cleavage site mapped by MS","pmids":["27716410"],"is_preprint":false},{"year":2013,"finding":"SEZ6L is a substrate of BACE1 (and not BACE2) in pancreatic beta-cells; ectodomain shedding of SEZ6L is regulated by BACE1 through a distinct, non-redundant mechanism from BACE2, as determined by loss- and gain-of-function proteomic studies.","method":"Quantitative proteomics (loss-of-function and gain-of-function in vitro and in vivo models, BACE1/2 knockout and overexpression)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — systematic quantitative proteomics with orthogonal loss/gain-of-function models","pmids":["23430253"],"is_preprint":false},{"year":2018,"finding":"Pharmacological BACE1 inhibition selectively increases SEZ6L abundance at the neuronal cell surface (up to 7-fold), confirming that BACE1 controls the surface proteome by shedding SEZ6L; surface changes only partly correlate with secretome changes.","method":"Click chemistry-mediated surface glycoprotein biotinylation (SUSPECS), quantitative mass spectrometry, immunoblot validation in neurons and mouse brains","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1-2 — novel surface proteomics method with multiple orthogonal validations","pmids":["29716987"],"is_preprint":false},{"year":2021,"finding":"The Sez6 family (including Sez6L) inhibits complement activation by (i) accelerating the decay of C3 convertases and (ii) acting as a cofactor for Factor I to facilitate cleavage of C3b, thereby reducing C3b/iC3b opsonization. Sez6L is a weak inhibitor of the classical pathway and its complement-regulatory activity was demonstrated using purified proteins.","method":"Complement opsonization assays, C3 convertase decay assays, Factor I cofactor activity assays with purified recombinant proteins","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro biochemical assays with purified proteins and multiple mechanistic readouts","pmids":["33936031"],"is_preprint":false},{"year":2021,"finding":"SEZ6L constitutive knockout mice display motor coordination deficits, gait changes, and increased anxiety-like behavior in adulthood, establishing that SEZ6L has a physiological role in regulating motor coordination and anxiety-related behavior in the nervous system.","method":"Constitutive knockout mouse model, behavioral testing (gait analysis, rotarod, Morris water maze, anxiety paradigms), cerebellar proteomics","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined behavioral phenotype and proteomics, replicated across multiple behavioral assays","pmids":["34958451"],"is_preprint":false},{"year":2020,"finding":"Sez6 family proteins (Sez6, Sez6L, Sez6L2) collectively regulate dendritic spine structure (density and morphology) in hippocampus and somatosensory cortex, and are required for motor learning, motor coordination, working memory, and spatial short-term memory, as shown in triple knockout (TKO) mice lacking all three family members.","method":"Sez6 triple knockout mice, dendritic spine morphology analysis, motor coordination and cognitive behavioral testing","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 — clean TKO with multiple orthogonal behavioral and morphological readouts","pmids":["31711114"],"is_preprint":false},{"year":2000,"finding":"SEZ6L encodes a 1024-amino-acid transmembrane protein containing multiple protein-protein interaction and signal transduction domains; its locus at 22q12.1 is homozygously deleted in a small cell lung carcinoma cell line, and missense mutations were detected in lung cancer cell lines, implicating SEZ6L as a candidate tumor suppressor at 22q12.1.","method":"Homozygous deletion mapping, RT-PCR, full-length cDNA cloning, GENSCAN gene prediction, sequencing of 46 lung cancer cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — structural characterization and deletion mapping provide domain/localization evidence, but functional role as tumor suppressor not directly validated","pmids":["11175339"],"is_preprint":false},{"year":2018,"finding":"In Niemann-Pick type C (NPC) disease, BACE1-mediated cleavage of Sez6L is elevated in multiple brain regions (cortex, hippocampus, cerebellum) at disease onset and terminal stage; Sez6L and APP co-localize in Purkinje neurons and their immunostaining is lost upon Purkinje cell neurodegeneration. In NPC primary cortical neurons, Sez6L shows increased punctate staining in the endolysosomal pathway coinciding with BACE1-positive puncta, indicating that endolysosomal trafficking defects drive enhanced BACE1 proteolysis of Sez6L.","method":"Immunoblotting of NPC1-/- mouse brain regions, immunofluorescence, primary cortical neuron staining, temporal analysis at 4 and 10 weeks","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple brain regions and time points in KO mice, but no direct functional rescue","pmids":["29979789"],"is_preprint":false},{"year":2013,"finding":"RNAi knockdown of SEZ6L in cells affects LDL internalization and/or cellular levels of free cholesterol, and overexpression of SEZ6L as a GFP fusion protein inversely modifies cellular cholesterol levels, placing SEZ6L as a functional regulator of cholesterol homeostasis.","method":"RNAi knockdown, LDL uptake assay, free cholesterol measurement, GFP-fusion overexpression, LDL-receptor level assessment","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — cell-based functional assays with both KD and OE but limited mechanistic pathway placement","pmids":["23468663"],"is_preprint":false},{"year":2022,"finding":"In 5xFAD Alzheimer's disease mouse brains, despite BACE1 accumulation in peri-plaque regions, proteolysis of Sez6 and Sez6L is not increased; instead, their subcellular distribution is altered in areas of Aβ plaques in a pattern distinct from APP, BACE1, and LAMP1, suggesting differential localization and function of these BACE1 substrates in the AD context.","method":"Immunoblotting, immunofluorescence in 5xFAD mouse brains at multiple ages","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization and proteolysis experiments in AD model, multiple substrates compared, but single study","pmids":["35998821"],"is_preprint":false}],"current_model":"SEZ6L is a neuronal single-pass transmembrane protein that is a physiological substrate of the protease BACE1, which cleaves SEZ6L near the membrane to shed its ectodomain and regulate its surface expression; the Sez6 family (including SEZ6L) also functions as a complement regulator by accelerating C3 convertase decay and serving as a Factor I cofactor for C3b cleavage, and SEZ6L is required in vivo for motor coordination, dendritic spine integrity, and anxiety regulation, with its endolysosomal trafficking modulating BACE1-mediated proteolysis."},"narrative":{"teleology":[{"year":2000,"claim":"The initial cloning of SEZ6L established it as a multi-domain transmembrane protein at 22q12.1, providing the structural framework for subsequent functional studies.","evidence":"Full-length cDNA cloning, domain prediction, and deletion/mutation mapping in lung cancer cell lines","pmids":["11175339"],"confidence":"Medium","gaps":["No direct functional validation of a tumor-suppressor role","Protein interaction partners not identified","Expression pattern across tissues not systematically characterized"]},{"year":2013,"claim":"Quantitative proteomic studies identified SEZ6L as a specific substrate of BACE1 (not BACE2), establishing that BACE1-mediated ectodomain shedding is the principal proteolytic mechanism acting on SEZ6L.","evidence":"Loss- and gain-of-function proteomics in pancreatic beta-cells with BACE1/2 knockout and overexpression models","pmids":["23430253"],"confidence":"High","gaps":["Neuronal BACE1 cleavage site not yet mapped","Functional consequence of shedding on SEZ6L signaling unknown"]},{"year":2013,"claim":"RNAi and overexpression experiments linked SEZ6L to cholesterol homeostasis, revealing a role in LDL internalization and free cholesterol regulation that extended its functional repertoire beyond neural tissue.","evidence":"RNAi knockdown, LDL uptake assays, free cholesterol measurement, and GFP-fusion overexpression in cell lines","pmids":["23468663"],"confidence":"Medium","gaps":["Mechanism connecting SEZ6L to LDL receptor trafficking not defined","Not independently replicated in a second study","Relevance to in vivo lipid metabolism not tested"]},{"year":2016,"claim":"Mass spectrometric mapping of the BACE1 cleavage site in SEZ6L near the transmembrane domain, combined with BACE1-KO mouse CSF proteomics, confirmed that BACE1 is the major sheddase for SEZ6L in neurons in vivo.","evidence":"Cell surface biotinylation in primary neurons, BACE1 inhibitor treatment, BACE1-KO mouse CSF proteomics, mass spectrometric cleavage-site mapping","pmids":["27716410"],"confidence":"High","gaps":["Biological function of the shed ectodomain (sSEZ6L) not determined","Fate and signaling capacity of the membrane-retained C-terminal fragment unknown"]},{"year":2018,"claim":"Surface proteomics showed that BACE1 inhibition causes dramatic (up to 7-fold) accumulation of SEZ6L at the neuronal surface, establishing SEZ6L as one of the most BACE1-sensitive surface proteins and clarifying that surface and secretome changes do not always correlate.","evidence":"Click chemistry–based surface glycoprotein biotinylation (SUSPECS), quantitative MS, immunoblot validation in neurons and mouse brains","pmids":["29716987"],"confidence":"High","gaps":["Functional consequence of increased surface SEZ6L on synaptic activity not tested","Whether surface accumulation alters complement regulation not examined"]},{"year":2018,"claim":"In Niemann-Pick type C disease, endolysosomal trafficking defects drive enhanced BACE1 proteolysis of SEZ6L, linking lipid storage disease pathology to dysregulated SEZ6L processing.","evidence":"Immunoblotting and immunofluorescence in NPC1-KO mouse brain regions and primary cortical neurons across disease stages","pmids":["29979789"],"confidence":"Medium","gaps":["No rescue experiment to confirm causality of endolysosomal defect","Whether enhanced SEZ6L shedding contributes to NPC neuropathology not established"]},{"year":2020,"claim":"Triple knockout of the Sez6 family demonstrated that these proteins are collectively required for dendritic spine integrity, motor learning, and cognitive functions, providing the first direct in vivo evidence of their synaptic structural role.","evidence":"Sez6/Sez6L/Sez6L2 triple knockout mice, dendritic spine morphology analysis, behavioral testing","pmids":["31711114"],"confidence":"High","gaps":["Individual contribution of SEZ6L versus Sez6 and Sez6L2 to spine phenotype not resolved","Molecular mechanism linking SEZ6L to spine maintenance unknown"]},{"year":2021,"claim":"Reconstituted biochemical assays demonstrated that SEZ6L inhibits complement activation by accelerating C3 convertase decay and acting as a Factor I cofactor for C3b cleavage, revealing a direct immune-modulatory function.","evidence":"C3 convertase decay assays, Factor I cofactor assays with purified recombinant SEZ6L","pmids":["33936031"],"confidence":"High","gaps":["In vivo complement-regulatory activity of SEZ6L specifically (versus other family members) not confirmed","Whether BACE1 shedding of SEZ6L modulates its complement-inhibitory function not tested","Structural basis of complement regulator activity not defined"]},{"year":2021,"claim":"SEZ6L knockout mice exhibited motor coordination deficits and anxiety-like behavior, establishing a non-redundant physiological role for SEZ6L in cerebellar and limbic circuit function.","evidence":"Constitutive SEZ6L-KO mice, gait analysis, rotarod, Morris water maze, anxiety paradigms, cerebellar proteomics","pmids":["34958451"],"confidence":"High","gaps":["Downstream molecular pathway mediating motor/anxiety phenotypes not identified","Whether complement dysregulation contributes to the behavioral phenotype unknown"]},{"year":2022,"claim":"In Alzheimer's disease model brains, SEZ6L shows altered subcellular distribution around amyloid plaques without increased BACE1-mediated proteolysis, indicating context-dependent regulation of SEZ6L processing distinct from APP.","evidence":"Immunoblotting and immunofluorescence in 5xFAD mouse brains at multiple ages","pmids":["35998821"],"confidence":"Medium","gaps":["Functional significance of altered SEZ6L distribution in AD pathology not determined","Whether peri-plaque SEZ6L affects local complement activation not tested","Single AD model without validation in human tissue"]},{"year":null,"claim":"Critical open questions remain: (1) the biological function of shed sSEZ6L, (2) whether BACE1-mediated shedding modulates the complement-regulatory activity of SEZ6L, (3) the molecular mechanism by which SEZ6L maintains dendritic spines and regulates motor coordination, and (4) the structural basis for SEZ6L's interaction with complement components.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of SEZ6L or its complement-regulatory domains available","Receptor or signaling function of the shed ectodomain undetermined","Integration of BACE1 processing and complement regulation not experimentally tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]}],"complexes":[],"partners":["BACE1","CFI","C3B"],"other_free_text":[]},"mechanistic_narrative":"SEZ6L is a single-pass transmembrane glycoprotein that functions as a physiological substrate of the protease BACE1 and as a regulator of complement activation in the nervous system. BACE1 cleaves SEZ6L near the transmembrane domain to shed its ectodomain, thereby controlling SEZ6L surface levels on neurons; pharmacological or genetic ablation of BACE1 causes up to 7-fold accumulation of SEZ6L at the cell surface and reduces soluble SEZ6L in cerebrospinal fluid [PMID:27716410, PMID:29716987]. SEZ6L also inhibits the complement cascade by accelerating C3 convertase decay and serving as a cofactor for Factor I–mediated cleavage of C3b [PMID:33936031]. In vivo, SEZ6L is required for motor coordination, normal gait, and regulation of anxiety-related behavior, and together with the other Sez6 family members it maintains dendritic spine density and morphology in hippocampus and cortex [PMID:34958451, PMID:31711114]."},"prefetch_data":{"uniprot":{"accession":"Q9BYH1","full_name":"Seizure 6-like protein","aliases":[],"length_aa":1024,"mass_kda":111.8,"function":"May contribute to specialized endoplasmic reticulum functions in neurons","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BYH1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEZ6L","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEZ6L","total_profiled":1310},"omim":[{"mim_id":"616667","title":"SEZ6-LIKE PROTEIN 2; SEZ6L2","url":"https://www.omim.org/entry/616667"},{"mim_id":"616666","title":"SEIZURE-RELATED 6, MOUSE, HOMOLOG OF; SEZ6","url":"https://www.omim.org/entry/616666"},{"mim_id":"608397","title":"CUB AND SUSHI MULTIPLE DOMAINS 1; CSMD1","url":"https://www.omim.org/entry/608397"},{"mim_id":"607295","title":"MYOSIN XVIIIB; MYO18B","url":"https://www.omim.org/entry/607295"},{"mim_id":"607021","title":"SEZ6-LIKE PROTEIN; SEZ6L","url":"https://www.omim.org/entry/607021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":46.3}],"url":"https://www.proteinatlas.org/search/SEZ6L"},"hgnc":{"alias_symbol":["SEZ6L1"],"prev_symbol":[]},"alphafold":{"accession":"Q9BYH1","domains":[{"cath_id":"2.60.120.290","chopping":"280-391","consensus_level":"high","plddt":83.2656,"start":280,"end":391},{"cath_id":"2.60.120.290","chopping":"403-624","consensus_level":"medium","plddt":86.7995,"start":403,"end":624},{"cath_id":"2.60.120.290","chopping":"627-741","consensus_level":"medium","plddt":85.2282,"start":627,"end":741},{"cath_id":"2.10.70.10","chopping":"755-803","consensus_level":"medium","plddt":84.9378,"start":755,"end":803},{"cath_id":"2.10.70.10","chopping":"816-868","consensus_level":"high","plddt":84.9268,"start":816,"end":868},{"cath_id":"2.10.70.10","chopping":"874-933","consensus_level":"high","plddt":84.716,"start":874,"end":933}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYH1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYH1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYH1-F1-predicted_aligned_error_v6.png","plddt_mean":68.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEZ6L","jax_strain_url":"https://www.jax.org/strain/search?query=SEZ6L"},"sequence":{"accession":"Q9BYH1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYH1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYH1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYH1"}},"corpus_meta":[{"pmid":"18158559","id":"PMC_18158559","title":"DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis.","date":"2007","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18158559","citation_count":145,"is_preprint":false},{"pmid":"27716410","id":"PMC_27716410","title":"Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.","date":"2016","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/27716410","citation_count":96,"is_preprint":false},{"pmid":"23430253","id":"PMC_23430253","title":"Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cells.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23430253","citation_count":81,"is_preprint":false},{"pmid":"26769141","id":"PMC_26769141","title":"High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing.","date":"2016","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/26769141","citation_count":48,"is_preprint":false},{"pmid":"23505291","id":"PMC_23505291","title":"Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers.","date":"2013","source":"Circulation. 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Gliomas","date":"2024-12-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.29.630486","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21435,"output_tokens":2518,"usd":0.051037},"stage2":{"model":"claude-opus-4-6","input_tokens":5828,"output_tokens":2516,"usd":0.13806},"total_usd":0.189097,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"SEZ6L is a physiological substrate of BACE1 (beta-secretase) in neurons: BACE1 cleaves SEZ6L near the membrane to release a soluble ectodomain (sSEZ6L); BACE1 inhibition increases neuronal surface levels of SEZ6L and reduces sSEZ6L in CSF of BACE1-deficient mice. Mass spectrometry mapped the BACE1 cleavage site in SEZ6L to a position close to the transmembrane domain.\",\n      \"method\": \"Cell surface biotinylation, primary neuron BACE1 inhibition, BACE1-knockout mouse CSF proteomics, antibody validation, mass spectrometric cleavage-site mapping\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro and in vivo methods, validated in primary neurons and BACE1-KO mice, cleavage site mapped by MS\",\n      \"pmids\": [\"27716410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEZ6L is a substrate of BACE1 (and not BACE2) in pancreatic beta-cells; ectodomain shedding of SEZ6L is regulated by BACE1 through a distinct, non-redundant mechanism from BACE2, as determined by loss- and gain-of-function proteomic studies.\",\n      \"method\": \"Quantitative proteomics (loss-of-function and gain-of-function in vitro and in vivo models, BACE1/2 knockout and overexpression)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic quantitative proteomics with orthogonal loss/gain-of-function models\",\n      \"pmids\": [\"23430253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pharmacological BACE1 inhibition selectively increases SEZ6L abundance at the neuronal cell surface (up to 7-fold), confirming that BACE1 controls the surface proteome by shedding SEZ6L; surface changes only partly correlate with secretome changes.\",\n      \"method\": \"Click chemistry-mediated surface glycoprotein biotinylation (SUSPECS), quantitative mass spectrometry, immunoblot validation in neurons and mouse brains\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel surface proteomics method with multiple orthogonal validations\",\n      \"pmids\": [\"29716987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Sez6 family (including Sez6L) inhibits complement activation by (i) accelerating the decay of C3 convertases and (ii) acting as a cofactor for Factor I to facilitate cleavage of C3b, thereby reducing C3b/iC3b opsonization. Sez6L is a weak inhibitor of the classical pathway and its complement-regulatory activity was demonstrated using purified proteins.\",\n      \"method\": \"Complement opsonization assays, C3 convertase decay assays, Factor I cofactor activity assays with purified recombinant proteins\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro biochemical assays with purified proteins and multiple mechanistic readouts\",\n      \"pmids\": [\"33936031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEZ6L constitutive knockout mice display motor coordination deficits, gait changes, and increased anxiety-like behavior in adulthood, establishing that SEZ6L has a physiological role in regulating motor coordination and anxiety-related behavior in the nervous system.\",\n      \"method\": \"Constitutive knockout mouse model, behavioral testing (gait analysis, rotarod, Morris water maze, anxiety paradigms), cerebellar proteomics\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined behavioral phenotype and proteomics, replicated across multiple behavioral assays\",\n      \"pmids\": [\"34958451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sez6 family proteins (Sez6, Sez6L, Sez6L2) collectively regulate dendritic spine structure (density and morphology) in hippocampus and somatosensory cortex, and are required for motor learning, motor coordination, working memory, and spatial short-term memory, as shown in triple knockout (TKO) mice lacking all three family members.\",\n      \"method\": \"Sez6 triple knockout mice, dendritic spine morphology analysis, motor coordination and cognitive behavioral testing\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean TKO with multiple orthogonal behavioral and morphological readouts\",\n      \"pmids\": [\"31711114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SEZ6L encodes a 1024-amino-acid transmembrane protein containing multiple protein-protein interaction and signal transduction domains; its locus at 22q12.1 is homozygously deleted in a small cell lung carcinoma cell line, and missense mutations were detected in lung cancer cell lines, implicating SEZ6L as a candidate tumor suppressor at 22q12.1.\",\n      \"method\": \"Homozygous deletion mapping, RT-PCR, full-length cDNA cloning, GENSCAN gene prediction, sequencing of 46 lung cancer cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — structural characterization and deletion mapping provide domain/localization evidence, but functional role as tumor suppressor not directly validated\",\n      \"pmids\": [\"11175339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Niemann-Pick type C (NPC) disease, BACE1-mediated cleavage of Sez6L is elevated in multiple brain regions (cortex, hippocampus, cerebellum) at disease onset and terminal stage; Sez6L and APP co-localize in Purkinje neurons and their immunostaining is lost upon Purkinje cell neurodegeneration. In NPC primary cortical neurons, Sez6L shows increased punctate staining in the endolysosomal pathway coinciding with BACE1-positive puncta, indicating that endolysosomal trafficking defects drive enhanced BACE1 proteolysis of Sez6L.\",\n      \"method\": \"Immunoblotting of NPC1-/- mouse brain regions, immunofluorescence, primary cortical neuron staining, temporal analysis at 4 and 10 weeks\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple brain regions and time points in KO mice, but no direct functional rescue\",\n      \"pmids\": [\"29979789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNAi knockdown of SEZ6L in cells affects LDL internalization and/or cellular levels of free cholesterol, and overexpression of SEZ6L as a GFP fusion protein inversely modifies cellular cholesterol levels, placing SEZ6L as a functional regulator of cholesterol homeostasis.\",\n      \"method\": \"RNAi knockdown, LDL uptake assay, free cholesterol measurement, GFP-fusion overexpression, LDL-receptor level assessment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — cell-based functional assays with both KD and OE but limited mechanistic pathway placement\",\n      \"pmids\": [\"23468663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In 5xFAD Alzheimer's disease mouse brains, despite BACE1 accumulation in peri-plaque regions, proteolysis of Sez6 and Sez6L is not increased; instead, their subcellular distribution is altered in areas of Aβ plaques in a pattern distinct from APP, BACE1, and LAMP1, suggesting differential localization and function of these BACE1 substrates in the AD context.\",\n      \"method\": \"Immunoblotting, immunofluorescence in 5xFAD mouse brains at multiple ages\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization and proteolysis experiments in AD model, multiple substrates compared, but single study\",\n      \"pmids\": [\"35998821\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEZ6L is a neuronal single-pass transmembrane protein that is a physiological substrate of the protease BACE1, which cleaves SEZ6L near the membrane to shed its ectodomain and regulate its surface expression; the Sez6 family (including SEZ6L) also functions as a complement regulator by accelerating C3 convertase decay and serving as a Factor I cofactor for C3b cleavage, and SEZ6L is required in vivo for motor coordination, dendritic spine integrity, and anxiety regulation, with its endolysosomal trafficking modulating BACE1-mediated proteolysis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEZ6L is a single-pass transmembrane glycoprotein that functions as a physiological substrate of the protease BACE1 and as a regulator of complement activation in the nervous system. BACE1 cleaves SEZ6L near the transmembrane domain to shed its ectodomain, thereby controlling SEZ6L surface levels on neurons; pharmacological or genetic ablation of BACE1 causes up to 7-fold accumulation of SEZ6L at the cell surface and reduces soluble SEZ6L in cerebrospinal fluid [PMID:27716410, PMID:29716987]. SEZ6L also inhibits the complement cascade by accelerating C3 convertase decay and serving as a cofactor for Factor I–mediated cleavage of C3b [PMID:33936031]. In vivo, SEZ6L is required for motor coordination, normal gait, and regulation of anxiety-related behavior, and together with the other Sez6 family members it maintains dendritic spine density and morphology in hippocampus and cortex [PMID:34958451, PMID:31711114].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The initial cloning of SEZ6L established it as a multi-domain transmembrane protein at 22q12.1, providing the structural framework for subsequent functional studies.\",\n      \"evidence\": \"Full-length cDNA cloning, domain prediction, and deletion/mutation mapping in lung cancer cell lines\",\n      \"pmids\": [\"11175339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct functional validation of a tumor-suppressor role\",\n        \"Protein interaction partners not identified\",\n        \"Expression pattern across tissues not systematically characterized\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Quantitative proteomic studies identified SEZ6L as a specific substrate of BACE1 (not BACE2), establishing that BACE1-mediated ectodomain shedding is the principal proteolytic mechanism acting on SEZ6L.\",\n      \"evidence\": \"Loss- and gain-of-function proteomics in pancreatic beta-cells with BACE1/2 knockout and overexpression models\",\n      \"pmids\": [\"23430253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Neuronal BACE1 cleavage site not yet mapped\",\n        \"Functional consequence of shedding on SEZ6L signaling unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"RNAi and overexpression experiments linked SEZ6L to cholesterol homeostasis, revealing a role in LDL internalization and free cholesterol regulation that extended its functional repertoire beyond neural tissue.\",\n      \"evidence\": \"RNAi knockdown, LDL uptake assays, free cholesterol measurement, and GFP-fusion overexpression in cell lines\",\n      \"pmids\": [\"23468663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting SEZ6L to LDL receptor trafficking not defined\",\n        \"Not independently replicated in a second study\",\n        \"Relevance to in vivo lipid metabolism not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mass spectrometric mapping of the BACE1 cleavage site in SEZ6L near the transmembrane domain, combined with BACE1-KO mouse CSF proteomics, confirmed that BACE1 is the major sheddase for SEZ6L in neurons in vivo.\",\n      \"evidence\": \"Cell surface biotinylation in primary neurons, BACE1 inhibitor treatment, BACE1-KO mouse CSF proteomics, mass spectrometric cleavage-site mapping\",\n      \"pmids\": [\"27716410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biological function of the shed ectodomain (sSEZ6L) not determined\",\n        \"Fate and signaling capacity of the membrane-retained C-terminal fragment unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Surface proteomics showed that BACE1 inhibition causes dramatic (up to 7-fold) accumulation of SEZ6L at the neuronal surface, establishing SEZ6L as one of the most BACE1-sensitive surface proteins and clarifying that surface and secretome changes do not always correlate.\",\n      \"evidence\": \"Click chemistry–based surface glycoprotein biotinylation (SUSPECS), quantitative MS, immunoblot validation in neurons and mouse brains\",\n      \"pmids\": [\"29716987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of increased surface SEZ6L on synaptic activity not tested\",\n        \"Whether surface accumulation alters complement regulation not examined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"In Niemann-Pick type C disease, endolysosomal trafficking defects drive enhanced BACE1 proteolysis of SEZ6L, linking lipid storage disease pathology to dysregulated SEZ6L processing.\",\n      \"evidence\": \"Immunoblotting and immunofluorescence in NPC1-KO mouse brain regions and primary cortical neurons across disease stages\",\n      \"pmids\": [\"29979789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No rescue experiment to confirm causality of endolysosomal defect\",\n        \"Whether enhanced SEZ6L shedding contributes to NPC neuropathology not established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Triple knockout of the Sez6 family demonstrated that these proteins are collectively required for dendritic spine integrity, motor learning, and cognitive functions, providing the first direct in vivo evidence of their synaptic structural role.\",\n      \"evidence\": \"Sez6/Sez6L/Sez6L2 triple knockout mice, dendritic spine morphology analysis, behavioral testing\",\n      \"pmids\": [\"31711114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contribution of SEZ6L versus Sez6 and Sez6L2 to spine phenotype not resolved\",\n        \"Molecular mechanism linking SEZ6L to spine maintenance unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstituted biochemical assays demonstrated that SEZ6L inhibits complement activation by accelerating C3 convertase decay and acting as a Factor I cofactor for C3b cleavage, revealing a direct immune-modulatory function.\",\n      \"evidence\": \"C3 convertase decay assays, Factor I cofactor assays with purified recombinant SEZ6L\",\n      \"pmids\": [\"33936031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo complement-regulatory activity of SEZ6L specifically (versus other family members) not confirmed\",\n        \"Whether BACE1 shedding of SEZ6L modulates its complement-inhibitory function not tested\",\n        \"Structural basis of complement regulator activity not defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SEZ6L knockout mice exhibited motor coordination deficits and anxiety-like behavior, establishing a non-redundant physiological role for SEZ6L in cerebellar and limbic circuit function.\",\n      \"evidence\": \"Constitutive SEZ6L-KO mice, gait analysis, rotarod, Morris water maze, anxiety paradigms, cerebellar proteomics\",\n      \"pmids\": [\"34958451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream molecular pathway mediating motor/anxiety phenotypes not identified\",\n        \"Whether complement dysregulation contributes to the behavioral phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In Alzheimer's disease model brains, SEZ6L shows altered subcellular distribution around amyloid plaques without increased BACE1-mediated proteolysis, indicating context-dependent regulation of SEZ6L processing distinct from APP.\",\n      \"evidence\": \"Immunoblotting and immunofluorescence in 5xFAD mouse brains at multiple ages\",\n      \"pmids\": [\"35998821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of altered SEZ6L distribution in AD pathology not determined\",\n        \"Whether peri-plaque SEZ6L affects local complement activation not tested\",\n        \"Single AD model without validation in human tissue\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Critical open questions remain: (1) the biological function of shed sSEZ6L, (2) whether BACE1-mediated shedding modulates the complement-regulatory activity of SEZ6L, (3) the molecular mechanism by which SEZ6L maintains dendritic spines and regulates motor coordination, and (4) the structural basis for SEZ6L's interaction with complement components.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of SEZ6L or its complement-regulatory domains available\",\n        \"Receptor or signaling function of the shed ectodomain undetermined\",\n        \"Integration of BACE1 processing and complement regulation not experimentally tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BACE1\",\n      \"CFI\",\n      \"C3b\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}