SEZ6 (seizure-related 6 homolog) is a brain-enriched single-pass type I transmembrane glycoprotein whose large extracellular region is built from CUB domains and complement control protein (sushi) repeats, with a short cytoplasmic tail. It is expressed on neurons, where it is found on dendrites and in synaptic and postsynaptic fractions, and it is a prominent substrate of the secretase BACE1, so a soluble ectodomain is shed into the extracellular space and cerebrospinal fluid. SEZ6 is thought to act in cell-cell recognition and neuronal membrane signalling - it balances dendrite elongation against branching during arbor elaboration and is required for appropriate excitatory synaptic connectivity and motor coordination, with Sez6-family-null mice showing dendritic, synaptic and behavioural deficits. Its surface expression on small-cell lung cancer and neuroendocrine tumours has made it an antibody-drug-conjugate and T-cell-engager target.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from a large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The single reported partner (UBQLN2) has no established functional significance for SEZ6, and no more specific molecular function can be justified from the interaction alone. |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SEZ6 is detected in the endoplasmic reticulum. Reason: As a secretory-pathway glycoprotein SEZ6 is translated, folded and glycosylated in the ER, and family members accumulate there; this is a biosynthetic compartment rather than the site where SEZ6 acts, which is the neuronal plasma membrane. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: SEZ6 is detected in the endoplasmic reticulum. Reason: As a secretory-pathway glycoprotein SEZ6 is translated, folded and glycosylated in the ER, and family members accumulate there; this is a biosynthetic compartment rather than the site where SEZ6 acts, which is the neuronal plasma membrane. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SEZ6 is a single-pass type I plasma membrane protein. Reason: The CUB and sushi domain ectodomain faces the extracellular space at the neuronal surface, where it is accessible to BACE1 cleavage and to therapeutic antibodies; UniProt records Cell membrane, single-pass type I. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein file:human/SEZ6/SEZ6-uniprot.txt Note=Localized on dendrites and in the synaptic and postsynaptic fraction. |
| GO:0008344 adult locomotory behavior | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Sez6-family loss impairs motor behaviour in mice. Reason: Locomotor phenotypes are organismal consequences of altered dendritic and synaptic development; rule-based transfer, retained as peripheral. |
| GO:0021680 cerebellar Purkinje cell layer development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: SEZ6 contributes to cerebellar Purkinje cell layer development. Reason: A region-specific developmental output of the dendrite and synapse functions, inferred by automated rules from rodent data. |
| GO:0043025 neuronal cell body | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SEZ6 is present in neuronal cell bodies. Reason: Consistent with the somatodendritic distribution of the protein, including its biosynthetic pool; less informative than the dendritic and plasma-membrane locations. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: SEZ6 is present in neuronal cell bodies. Reason: Consistent with the somatodendritic distribution of the protein, including its biosynthetic pool; less informative than the dendritic and plasma-membrane locations. |
| GO:0043197 dendritic spine | IBA GO_REF:0000033 | ACCEPT | Summary: SEZ6 is present in dendritic spines. Reason: The protein is localized on dendrites and recovered in synaptic and postsynaptic fractions, consistent with the phylogenetic inference for the family, and this is where its synaptic function is exercised. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Note=Localized on dendrites and in the synaptic and postsynaptic fraction. |
| GO:0043197 dendritic spine | IEA GO_REF:0000107 | ACCEPT | Summary: SEZ6 is present in dendritic spines. Reason: The protein is localized on dendrites and recovered in synaptic and postsynaptic fractions, consistent with the phylogenetic inference for the family, and this is where its synaptic function is exercised. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Note=Localized on dendrites and in the synaptic and postsynaptic fraction. |
| GO:0043198 dendritic shaft | IBA GO_REF:0000033 | ACCEPT | Summary: SEZ6 is present along dendritic shafts. Reason: Dendritic localization is directly recorded for the protein and matches its role in balancing dendrite elongation and branching. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Note=Localized on dendrites and in the synaptic and postsynaptic fraction. |
| GO:0043198 dendritic shaft | IEA GO_REF:0000107 | ACCEPT | Summary: SEZ6 is present along dendritic shafts. Reason: Dendritic localization is directly recorded for the protein and matches its role in balancing dendrite elongation and branching. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Note=Localized on dendrites and in the synaptic and postsynaptic fraction. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perinuclear signal attributed to SEZ6. Reason: Most likely reflects the biosynthetic (ER/Golgi) pool of a secretory-pathway membrane protein; peripheral to its site of action. |
| GO:0050773 regulation of dendrite development | IBA GO_REF:0000033 | ACCEPT | Summary: SEZ6 regulates dendrite development. Reason: The protein sets the balance between dendrite elongation and branching during arbor elaboration; this is its best-supported biological role and matches the PAINT node placement for the SEZ6 family. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Seems to be important for the achievement of the necessary balance between dendrite elongation and branching during the elaboration of a complex dendritic arbor. |
| GO:0060074 synapse maturation | IBA GO_REF:0000033 | ACCEPT | Summary: SEZ6 is required for maturation of excitatory synapses. Reason: Loss of SEZ6 family function impairs development of appropriate excitatory synaptic connectivity, and the protein is enriched in postsynaptic fractions. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Involved in the development of appropriate excitatory synaptic connectivity |
| GO:0060074 synapse maturation | IEA GO_REF:0000117 | ACCEPT | Summary: SEZ6 is required for maturation of excitatory synapses. Reason: Loss of SEZ6 family function impairs development of appropriate excitatory synaptic connectivity, and the protein is enriched in postsynaptic fractions. Supporting Evidence: file:human/SEZ6/SEZ6-uniprot.txt Involved in the development of appropriate excitatory synaptic connectivity |
| GO:0097440 apical dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SEZ6 is present in apical dendrites. Reason: A specific dendritic subcompartment consistent with the general dendritic localization; electronically transferred, retained as non-core. |
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Download this section (compressed HTML)Q: What is the molecular activity of SEZ6 - does its CUB/sushi ectodomain bind a specific extracellular ligand or a trans-synaptic partner, and is a receptor or adhesion term justified?
Q: Is the BACE1-shed SEZ6 ectodomain biologically active, for example as a diffusible regulator of dendrite branching, or is shedding purely a down-regulation mechanism?
Q: How do SEZ6, SEZ6L and SEZ6L2 divide the dendritic and synaptic functions of the family, and what accounts for the human cerebellar ataxia phenotypes associated with SEZ6 variants?
Experiment: Unbiased surface interactome screening (cell-surface two-hybrid or avidity-based extracellular interaction screening) with the SEZ6 ectodomain, to identify the ligand or trans-synaptic partner that would justify a specific molecular function term.
Experiment: Structure-function analysis of CUB versus sushi domain deletions re-expressed in SEZ6-null human neurons, scoring dendritic branching and excitatory synapse density.
Experiment: Acute application of purified shed SEZ6 ectodomain to developing neurons, with and without membrane-anchored SEZ6, to test whether the soluble fragment has signalling activity.
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