Affinage

SEZ6L

Seizure 6-like protein · UniProt Q9BYH1

Length
1024 aa
Mass
111.8 kDa
Annotated
2026-04-28
34 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 Medium

    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

    PMID:11175339

    Open questions at the time
    • No direct functional validation of a tumor-suppressor role
    • Protein interaction partners not identified
    • Expression pattern across tissues not systematically characterized
  2. 2013 High

    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

    PMID:23430253

    Open questions at the time
    • Neuronal BACE1 cleavage site not yet mapped
    • Functional consequence of shedding on SEZ6L signaling unknown
  3. 2013 Medium

    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

    PMID:23468663

    Open questions at the time
    • Mechanism connecting SEZ6L to LDL receptor trafficking not defined
    • Not independently replicated in a second study
    • Relevance to in vivo lipid metabolism not tested
  4. 2016 High

    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

    PMID:27716410

    Open questions at the time
    • Biological function of the shed ectodomain (sSEZ6L) not determined
    • Fate and signaling capacity of the membrane-retained C-terminal fragment unknown
  5. 2018 High

    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

    PMID:29716987

    Open questions at the time
    • Functional consequence of increased surface SEZ6L on synaptic activity not tested
    • Whether surface accumulation alters complement regulation not examined
  6. 2018 Medium

    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

    PMID:29979789

    Open questions at the time
    • No rescue experiment to confirm causality of endolysosomal defect
    • Whether enhanced SEZ6L shedding contributes to NPC neuropathology not established
  7. 2020 High

    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

    PMID:31711114

    Open questions at the time
    • Individual contribution of SEZ6L versus Sez6 and Sez6L2 to spine phenotype not resolved
    • Molecular mechanism linking SEZ6L to spine maintenance unknown
  8. 2021 High

    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

    PMID:33936031

    Open questions at the time
    • 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
  9. 2021 High

    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

    PMID:34958451

    Open questions at the time
    • Downstream molecular pathway mediating motor/anxiety phenotypes not identified
    • Whether complement dysregulation contributes to the behavioral phenotype unknown
  10. 2022 Medium

    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

    PMID:35998821

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 1
Partners
BACE1C3BCFI

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 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. Cell surface biotinylation, primary neuron BACE1 inhibition, BACE1-knockout mouse CSF proteomics, antibody validation, mass spectrometric cleavage-site mapping Molecular neurodegeneration High 27716410
2013 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. Quantitative proteomics (loss-of-function and gain-of-function in vitro and in vivo models, BACE1/2 knockout and overexpression) The Journal of biological chemistry High 23430253
2018 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. Click chemistry-mediated surface glycoprotein biotinylation (SUSPECS), quantitative mass spectrometry, immunoblot validation in neurons and mouse brains Molecular & cellular proteomics : MCP High 29716987
2021 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. Complement opsonization assays, C3 convertase decay assays, Factor I cofactor activity assays with purified recombinant proteins Frontiers in immunology High 33936031
2021 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. Constitutive knockout mouse model, behavioral testing (gait analysis, rotarod, Morris water maze, anxiety paradigms), cerebellar proteomics Molecular neurobiology High 34958451
2020 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. Sez6 triple knockout mice, dendritic spine morphology analysis, motor coordination and cognitive behavioral testing Cerebral cortex High 31711114
2000 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. Homozygous deletion mapping, RT-PCR, full-length cDNA cloning, GENSCAN gene prediction, sequencing of 46 lung cancer cell lines Oncogene Medium 11175339
2018 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. Immunoblotting of NPC1-/- mouse brain regions, immunofluorescence, primary cortical neuron staining, temporal analysis at 4 and 10 weeks PloS one Medium 29979789
2013 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. RNAi knockdown, LDL uptake assay, free cholesterol measurement, GFP-fusion overexpression, LDL-receptor level assessment PLoS genetics Medium 23468663
2022 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. Immunoblotting, immunofluorescence in 5xFAD mouse brains at multiple ages Mechanisms of ageing and development Medium 35998821

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Laboratory investigation; a journal of technical methods and pathology 145 18158559
2016 Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Molecular neurodegeneration 96 27716410
2013 Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cells. The Journal of biological chemistry 81 23430253
2016 High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 48 26769141
2013 RNAi-based functional profiling of loci from blood lipid genome-wide association studies identifies genes with cholesterol-regulatory function. PLoS genetics 46 23468663
2013 Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers. Circulation. Cardiovascular genetics 46 23505291
2020 Lack of Sez6 Family Proteins Impairs Motor Functions, Short-Term Memory, and Cognitive Flexibility and Alters Dendritic Spine Properties. Cerebral cortex (New York, N.Y. : 1991) 45 31711114
2016 IL-10 and integrin signaling pathways are associated with head and neck cancer progression. BMC genomics 43 26747525
2000 Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line. Oncogene 39 11175339
2023 Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity. Brain : a journal of neurology 33 36448302
2021 The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases. Frontiers in immunology 32 33936031
2016 Genomic Regions Associated With Interspecies Communication in Dogs Contain Genes Related to Human Social Disorders. Scientific reports 30 27685260
2018 Click Chemistry-mediated Biotinylation Reveals a Function for the Protease BACE1 in Modulating the Neuronal Surface Glycoproteome. Molecular & cellular proteomics : MCP 29 29716987
2007 Seizure 6-like (SEZ6L) gene and risk for lung cancer. Cancer research 27 17804757
2021 Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF. International journal of molecular sciences 22 34360799
2012 Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene × gender interaction. Journal of affective disorders 21 22920719
2022 Characterization of Different Subtypes of Immune Cell Infiltration in Glioblastoma to Aid Immunotherapy. Frontiers in immunology 14 35799789
2018 BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains. PloS one 14 29979789
2020 Arsenic Exposure and Cancer-Related Proteins in Urine of Indigenous Bolivian Women. Frontiers in public health 13 33381488
2022 Insight Into Pituitary lncRNA and mRNA at Two Estrous Stages in Small Tail Han Sheep With Different FecB Genotypes. Frontiers in endocrinology 12 35178025
2015 Genomic Study of Cardiovascular Continuum Comorbidity. Acta naturae 12 26483964
2022 Development of a Multiprotein Classifier for the Detection of Early Stage Ovarian Cancer. Cancers 9 35804849
2021 The β-Secretase Substrate Seizure 6-Like Protein (SEZ6L) Controls Motor Functions in Mice. Molecular neurobiology 9 34958451
2024 Identification of endocrine-disrupting chemicals targeting key DCM-associated genes via bioinformatics and machine learning. Ecotoxicology and environmental safety 7 38460409
2024 Cell Fate Dynamics Reconstruction Identifies TPT1 and PTPRZ1 Feedback Loops as Master Regulators of Differentiation in Pediatric Glioblastoma-Immune Cell Networks. Interdisciplinary sciences, computational life sciences 5 39420135
2025 Joint analysis of whole-genome methylation and transcriptome in avian pullorum disease and validation of gene function. BMC genomics 2 40597609
2024 Genetic background of walking ability and its relationship with leg defects, mortality, and performance traits in turkeys (Meleagris gallopavo). Poultry science 2 38788487
2025 Effects of Oral Administration of the Probiotic Lactobacillus rhamnosus GG on the Proteomic Profiles of Cerebrospinal Fluid and Immunoregulatory Signaling in the Hippocampus of Adult Male Rats. Neuroimmunomodulation 1 40031897
2025 Deep learning-based feature discovery for decoding phenotypic plasticity in pediatric high-grade gliomas single-cell transcriptomics. Computers in biology and medicine 1 40848317
2025 Single-nuclei RNA sequencing unveils astrocyte and oligodendrocyte lineage cells in post-stroke human brain. Experimental neurology 1 41238151
2022 Amyloid-ß plaque formation and BACE1 accumulation in the brains of a 5xFAD Alzheimer's disease mouse model is associated with altered distribution and not proteolysis of BACE1 substrates Sez6 and Sez6L. Mechanisms of ageing and development 1 35998821
2026 SEZ6L2 Loss Disrupts Motor Coordination, Cognitive Function, and Synaptic Connectivity. bioRxiv : the preprint server for biology 0 41502956
2026 Genome-wide association study identifies GAK and KLF12 associated with curve severity of adolescent idiopathic scoliosis. PeerJ 0 41584833
2022 A Proteomics Study of the Subacute Toxicity of Rat Brain after Long- Term Exposure of Gelsemium elegans. Current molecular pharmacology 0 34886788