Seizure-related 6 homolog protein (SEZ6)

Seizure-related 6 homolog protein (SEZ6) is a transmembrane protein with three CUB domains and five short consensus repeat domains, primarily expressed in the central nervous system where it plays crucial roles in neuronal development, synaptic plasticity, and immune regulation[2][3]. SEZ6 is an exclusive substrate of the protease BACE1, making it a key player in understanding BACE1 biology relevant to Alzheimer's disease and potentially useful as a biomarker for BACE1 activity in cerebrospinal fluid[3][5]. The protein is involved in regulating dendritic spine morphology, excitatory synapse formation, and complement cascade inhibition[2][3][7]. Genetic variants in SEZ6 have been associated with seizure susceptibility and epilepsy, while aberrant expression is linked to schizophrenia and other neuropsychiatric disorders[2]. Notably, SEZ6 is uniquely and highly expressed in neuroendocrine carcinomas, particularly small cell lung cancer with neuroendocrine-high profiles, making it a potential diagnostic and prognostic biomarker for these tumors[2]. While SEZ6 has been nominated as a tumor-selective therapeutic target in neuroendocrine malignancies, its precise role in cancer biology remains to be determined, and its functional role in normal physiology as well as disease states continues to be actively investigated[2].

Other names

Seizure protein 6Seizure-related protein 6

SEZ6 functions through several mechanisms: - **BACE1-mediated ectodomain shedding:** SEZ6 is an exclusive BACE1 substrate, meaning its ectodomain cleavage is almost exclusively dependent on BACE1 activity[1]. Unlike most other BACE1 substrates, other proteases do not compensate when BACE1 is inhibited[3]. - **Intracellular signaling:** SEZ6 may trigger intracellular signaling via its cytoplasmic NPxY motif, a phosphotyrosine-binding domain-containing protein interaction motif that mediates internalization from the cell surface[3]. The intracellular domain is subsequently released from the membrane by γ-secretase through regulated intramembrane proteolysis[3]. - **Surface expression regulation:** BACE1 activity fine-tunes the balance between cell-surface and shed forms of SEZ6, controlling surface expression levels[5].