Affinage

SEZ6

Seizure protein 6 homolog · UniProt Q53EL9

Length
994 aa
Mass
107.4 kDa
Annotated
2026-04-28
25 papers in source corpus 13 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEZ6 is a type I transmembrane glycoprotein that regulates dendritic arborization, spine density, and excitatory synaptic connectivity in the developing brain while also functioning as a complement pathway inhibitor. Its ectodomain contains five CCP/SCR domains and two CUB-like repeats; alternative splicing generates membrane-bound and secreted isoforms that exert opposing effects on dendritic branching—membrane-bound Sez6 suppresses branching whereas secreted Sez6 promotes it—and loss of Sez6 in knockout mice results in excess short dendrites, reduced spine density, diminished PSD-95 puncta, and attenuated excitatory postsynaptic responses (PMID:18031681, PMID:31711114). SEZ6 family members inhibit C3b opsonization by accelerating C3 convertase decay and serving as cofactors for Factor I–mediated cleavage of C3b, establishing a direct role in complement regulation at the neuronal surface (PMID:33936031). The transmembrane isoform is a BACE1 substrate whose ectodomain shedding releases a soluble fragment detectable in cerebrospinal fluid, and N-glycosylation of specific CCP clusters governs cell-surface distribution and neurite-promoting activity (PMID:29979789, PMID:25960298).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1995 High

    Cloning of SEZ6 revealed a novel transmembrane architecture with complement-related CCP/SCR and CUB domains, establishing that a seizure-responsive gene encodes a protein with potential complement-signaling and cell-recognition functions.

    Evidence cDNA cloning, sequence analysis, and domain prediction from seizure-induced brain libraries; in vitro translation and immunoblot confirmed glycosylation and multiple isoforms including a secreted form

    PMID:7488116 PMID:7723619

    Open questions at the time
    • No functional assay for complement binding or cell recognition
    • Ligand or binding partner unknown
    • Isoform-specific functions not tested
  2. 2007 High

    Knockout mouse studies answered the question of SEZ6's neuronal function, demonstrating that it is required for normal dendritic arborization, spine density, and excitatory synaptic connectivity, with membrane-bound and secreted isoforms exerting opposing effects on branching.

    Evidence Sez6 null mutant mice, isoform-specific rescue in cultured KO neurons, electrophysiology, PSD-95 immunostaining

    PMID:18031681

    Open questions at the time
    • Molecular mechanism by which membrane-bound Sez6 inhibits branching is unknown
    • Direct binding partners mediating dendritic effects not identified
    • Signaling pathways downstream of Sez6 at the membrane not defined
  3. 2011 Medium

    Developmental relocalization of Sez6 protein from dendrites to the perisomatic region after postnatal day 10 indicated a temporal shift in function, while a separate study linked Sez6 to PKCγ-dependent neurite outgrowth.

    Evidence Immunohistochemistry with validated antibody across postnatal time points; shRNA knockdown in PC12 cells with PKCγ Western blot

    PMID:21334315 PMID:22351987

    Open questions at the time
    • Functional consequence of relocalization not directly tested
    • PKCγ link based on correlation without direct epistasis experiments
    • Whether PKCγ pathway operates in primary neurons is untested
  4. 2015 Medium

    Site-directed mutagenesis of N-glycosylation clusters showed that specific glycan modifications regulate Sez6 cell-surface distribution and filopodia formation, providing the first post-translational mechanism controlling its activity.

    Evidence Glycosylation cluster deletion mutants in Neuro2a cells with surface distribution and morphology analysis

    PMID:25960298

    Open questions at the time
    • Not validated in primary neurons
    • How glycosylation affects ligand binding or complement function unknown
    • Whether glycosylation modulates BACE1 cleavage site accessibility not tested
  5. 2018 Medium

    Identification of SEZ6 as a BACE1 substrate answered how its ectodomain is shed, and revealed that endolysosomal trafficking defects (as in NPC1 deficiency) enhance BACE1-mediated cleavage.

    Evidence Immunoblot of BACE1 cleavage products in NPC1-null versus wild-type mouse brains; endolysosomal colocalization in primary cortical neurons

    PMID:29979789

    Open questions at the time
    • BACE1 cleavage site on Sez6 not mapped
    • Functional consequence of enhanced shedding in NPC1 disease context not determined
    • Whether soluble ectodomain retains complement-inhibitory activity unknown
  6. 2019 Medium

    Detection of shed Sez6 ectodomain in human CSF and attenuated pain behavior in Sez6 knockout mice extended SEZ6 function beyond dendritic development to peripheral nociceptive signaling.

    Evidence Western blot of CSF from surgical patients; behavioral analysis of Sez6 knockout mice after peripheral nerve injury

    PMID:31041421

    Open questions at the time
    • Mechanism linking Sez6 to pain signaling not identified
    • Whether CSF Sez6 is functionally active or a degradation product unknown
    • Cell types contributing to CSF Sez6 not determined
  7. 2020 High

    Triple knockout of all Sez6 family members established that the family collectively and non-redundantly regulates spine density, spine maturation, motor learning, and cognitive flexibility.

    Evidence Sez6/Sez6L/Sez6L2 triple knockout mice with spine morphology analysis and behavioral testing

    PMID:31711114

    Open questions at the time
    • Individual contributions of each family member to spine phenotype not fully dissected
    • Downstream signaling pathways shared or distinct among family members unknown
    • Whether complement inhibition contributes to spine phenotypes not tested
  8. 2021 High

    Biochemical reconstitution demonstrated that SEZ6 family proteins are bona fide complement inhibitors that accelerate C3 convertase decay and serve as Factor I cofactors for C3b cleavage, finally assigning a molecular activity to the CCP domains.

    Evidence Classical and alternative pathway opsonization assays, C3 convertase decay acceleration assay, Factor I cofactor assay with purified components

    PMID:33936031

    Open questions at the time
    • Whether complement inhibition occurs in vivo on neuronal surfaces not shown
    • Relative potency of Sez6 versus Sez6L2 in complement assays not directly compared
    • Structural basis for C3b selectivity over C4b unknown
  9. 2022 Medium

    Studies in AD mouse models, isoform splicing analysis, and antibody-drug conjugate work collectively refined the understanding of Sez6 processing and trafficking: Sez6 shows altered peri-plaque distribution without enhanced cleavage in 5xFAD mice, brain-region-specific alternative splicing, and efficient internalization from the cell surface upon antibody binding.

    Evidence Western blot and immunofluorescence in 5xFAD brains; qPCR of isoform-specific primers across brain regions; antibody internalization assays in SCLC cell lines with in vivo ADC efficacy

    PMID:35642431 PMID:35998821 PMID:36368155

    Open questions at the time
    • Mechanism of Sez6 redistribution around amyloid plaques not defined
    • Functional significance of brain-region-specific splicing patterns untested
    • Internalization pathway and endosomal routing upon antibody binding not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: what are the direct binding partners through which membrane-bound Sez6 regulates dendritic branching and spine density, whether complement inhibition by Sez6 at the neuronal surface contributes to synapse protection in vivo, and what the structural basis is for isoform-specific opposing functions.
  • No direct neuronal binding partner identified for dendritic phenotype
  • In vivo complement inhibition at synapses not demonstrated
  • No structural model of Sez6 ectodomain exists
  • Relationship between BACE1 shedding and complement-inhibitory function not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 2 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 1
Partners
BACE1C3BCFISEZ6LSEZ6L2

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 SEZ6 encodes a type I transmembrane protein with a signal sequence, threonine-rich domain, five complement control protein (CCP/SCR) domains (complement C3b/C4b binding sites), two CUB domain-like repeats, one transmembrane domain, and a short cytoplasmic tail, suggesting roles in complement-related signaling and cell-cell recognition. cDNA cloning, sequence analysis, domain prediction Brain research. Molecular brain research High 7488116 7723619
1995 SEZ6 protein is post-translationally modified (glycosylated) and expressed in cerebrum and cerebellum; PCR identified two additional isoforms: one encoding a membrane protein with a different C-terminal region and one encoding a secreted protein with two SCRs and one CUB-like domain. In vitro translation, immunoblot with anti-SEZ6 peptide antibody, PCR isoform analysis Biochemical and biophysical research communications High 7488116
2007 Sez6 is required for normal dendritic arborization of cortical pyramidal neurons; loss of Sez6 in null mice causes excess short dendrites and excessive neurite branching in cultured neurons. Membrane-bound Sez6 exerts an anti-branching effect while secreted Sez6 has opposing (pro-branching) activity. Layer V pyramidal neurons in knockout mice show reduced excitatory postsynaptic responses and reduced dendritic spine density with diminished PSD-95 puncta. Sez6 null mutant mouse analysis, overexpression of individual isoforms in knockout neurons, electrophysiology, immunostaining for PSD-95, cultured neuron assays Neuron High 18031681
2007 Membrane-bound and secreted Sez6 isoforms have opposing effects on dendritic branching, with cell-surface protein complexes involving Sez6 sculpting the dendritic arbor and enhancing synaptic connectivity. Overexpression of individual Sez6 isoforms in sez-6 knockout cortical neurons under basal and depolarizing conditions Neuron High 18031681
2011 Sez6 protein localizes to dendrites of hippocampal and cortical pyramidal neurons neonatally, then relocates perisomatic after postnatal day 10, suggesting a developmental shift in function during forebrain maturation. Immunohistochemistry with new anti-Sez6 antibody validated by Western blot, temporal and spatial expression analysis Brain research Medium 21334315
2011 Sez-6 promotes neurite outgrowth in PC12 cells via a mechanism involving PKCγ signaling; knockdown of Sez-6 by shRNA inhibits neurite outgrowth and increases PKCγ protein levels in differentiated cells. shRNA knockdown in PC12 cells, NGF differentiation, Western blot for PKCγ Zeitschrift fur Naturforschung. C, Journal of biosciences Low 22351987
2015 N-glycosylation of Sez6 regulates its cell-surface distribution and function; the SC4-7 glycosylation cluster is specifically required for filopodia-like protrusion formation, while removal of SC1-3 or SC4-7 clusters reduces neurite formation. Unglycosylated Sez6 is still transported to the membrane but shows altered distribution. N-glycosylation cluster deletion mutants transfected into Neuro2a cells, cell surface distribution analysis, conditioned medium analysis Biochemical and biophysical research communications Medium 25960298
2018 Sez6 is a substrate of BACE1 (β-secretase); BACE1 cleaves the type I transmembrane isoform of Sez6, shedding its extracellular domain from the neuron surface. Enhanced BACE1-cleavage of Sez6 and Sez6L is detected in NPC1-null mouse brains. Sez6 and Sez6L show increased punctate staining within the endolysosomal pathway in NPC1-null neurons, indicating a trafficking defect underlies enhanced BACE1 proteolysis. Immunoblot of BACE1 cleavage products in NPC1-null vs. wild-type mouse brains, immunofluorescence of endolysosomal colocalization in primary cortical neurons PloS one Medium 29979789
2019 The BACE1-shed extracellular domain of Sez6 is detectable in human cerebrospinal fluid, and Sez6 levels are elevated in CSF of patients with inflammatory pain conditions. Sez6 knockout mice show attenuated pain behaviors after peripheral nerve injury. Western blot of CSF from surgical patients; behavioral analysis of sez6 knockout mice after nerve injury Pain reports Medium 31041421
2020 Sez6 family proteins (Sez6, Sez6L, Sez6L2) collectively regulate dendritic spine structure and density; triple knockout (TKO) mice lacking all three family members show reduced hippocampal spine density and shift toward immature spine morphologies in somatosensory cortex, along with impaired motor learning and cognitive flexibility. Sez6 triple knockout mice, spine morphology analysis, behavioral testing (motor coordination, Morris water maze, working memory) Cerebral cortex High 31711114
2021 Sez6, Sez6L, and Sez6L2 function as complement inhibitors: they inhibit C3b/iC3b opsonization by the classical and alternative complement pathways. Using Sez6L2 as representative, the family accelerates dissociation of C3 convertases and acts as a cofactor for Factor I to facilitate cleavage of C3b (but not C4b). Complement inhibition assays (classical and alternative pathway opsonization), C3 convertase decay assay, Factor I cofactor assay Frontiers in immunology High 33936031
2022 In 5xFAD Alzheimer's disease mouse brains, BACE1 accumulation in peri-plaque regions does not enhance proteolytic cleavage of Sez6 or Sez6L, but both proteins show altered distribution in areas surrounding Aβ plaques, distinct from APP/BACE1/LAMP1 localization. Western blot for Sez6/Sez6L cleavage products in 5xFAD brains, immunofluorescence localization relative to Aβ plaques Mechanisms of ageing and development Medium 35998821
2022 Sez6 alternative splicing produces three isoforms (dominant transmembrane, and two recessive isoforms including a secreted form) with brain-area-specific splicing patterns; the striatum shows a characteristic recessive isoform pattern. Neuronal activation by convulsant drug increases recessive isoforms similarly to the dominant isoform in cultured cortical neurons. qPCR of isoform-specific primers across brain regions and cultured cortical neurons under convulsant stimulation Biochemical and biophysical research communications Low 36368155
2022 SEZ6 is rapidly internalized upon antibody binding to its extracellular domain on the cell surface, enabling antibody-drug conjugate payload delivery in SCLC cells. Antibody internalization assay in SEZ6-expressing SCLC cell lines, in vitro and in vivo ADC efficacy Molecular cancer therapeutics Medium 35642431

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons. Neuron 121 18031681
2022 ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors. Molecular cancer therapeutics 50 35642431
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
1995 Cloning and expression of SEZ-6, a brain-specific and seizure-related cDNA. Brain research. Molecular brain research 41 7723619
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
1995 Cloning and characterization of seizure-related gene, SEZ-6. Biochemical and biophysical research communications 32 7488116
2002 Localized expression of the seizure-related gene SEZ-6 in developing and adult forebrains. Mechanisms of development 25 12351182
2011 The distribution of the seizure-related gene 6 (Sez-6) protein during postnatal development of the mouse forebrain suggests multiple functions for this protein: an analysis using a new antibody. Brain research 22 21334315
2011 The Role of Seizure-Related SEZ6 as a Susceptibility Gene in Febrile Seizures. Neurology research international 20 21785725
1997 SEZ-6: promoter selectivity, genomic structure and localized expression in the brain. Brain research. Molecular brain research 19 9073173
2018 BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains. PloS one 14 29979789
2021 ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment. European journal of human genetics : EJHG 12 34135477
2018 Exome sequencing in an Italian family with Alzheimer's disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H. Alzheimer's research & therapy 12 30309378
2009 Seizure-related gene 6 (Sez-6) in amacrine cells of the rodent retina and the consequence of gene deletion. PloS one 10 19662096
2019 Sez6 levels are elevated in cerebrospinal fluid of patients with inflammatory pain-associated conditions. Pain reports 8 31041421
2024 Preclinical Characterization of Catabolic Pathways and Metabolism of ABBV-011, a Novel Calicheamicin-Based SEZ6-Targeting Antibody-Drug Conjugate. Drug metabolism and disposition: the biological fate of chemicals 5 38050039
2025 Detection of SEZ6, a Therapeutic Target, in Medullary Thyroid Carcinoma. The Journal of clinical endocrinology and metabolism 4 39324657
2015 N-Glycosylation modulates filopodia-like protrusions induced by sez-6 through regulating the distribution of this protein on the cell surface. Biochemical and biophysical research communications 3 25960298
2025 Expression of DLL3 and SEZ6 in the Spectrum of Neuroendocrine Neoplasia. Endocrine pathology 2 40699376
2025 Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 2 40911432
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
2011 Sez-6 may play an important role in neurite outgrowth through the PKCgamma signaling pathways. Zeitschrift fur Naturforschung. C, Journal of biosciences 1 22351987
2026 SEZ6 expression and lineage plasticity in small cell lung cancer and transformed non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 0 41534317
2026 Novel ImmunoPET Probes [64Cu]Cu-NOTA-GGB02-F9 for Small-Cell Lung Cancer Derived from a SEZ6-Targeting Antibody. Journal of medicinal chemistry 0 41589586
2022 Differential brain expression pattern of Sez6 alternative splicing isoform with deleted transmembrane domain. Biochemical and biophysical research communications 0 36368155