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Seizure-6 proteins highlight BACE1 functions in neurobiology

Oncotarget. 2016 Dec 5. doi: 10.18632/oncotarget.13801. [Epub ahead of print]

Authors/Editors: Pigoni M, Gunnersen JM, Lichtenthaler SF.
Publication Date: 2016

2016_12_pigoni

Abstract

Proteins of the Seizure protein 6 (Sez6) family are abundant in neurons and are localized to the somatodendritic compartment of these highly polarised cells (Gunnersen et al., 2007; Miyazaki et al., 2006). Two recent studies (Kuhn et al., 2012; Pigoni et al., 2016) highlight the important role of the Alzheimer’s disease (AD)-linked aspartyl-protease β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) in the regulation of Sez6 and Sez6-like (Sez6L), influencing their sub-cellular distribution and, presumably, their function.

The three members of the Sez6 family of proteins, which also includes Sez6L2, are single transmembrane domain proteins with large extracellular regions (Figure 1). The presence of multiple CUB and SCR (also termed CCP or sushi) domains suggests adhesive and/or receptor trafficking functions of these proteins, however their binding partners are not yet known. Sez6 proteins may trigger intracellular signaling via their cytoplasmic NPxY motif, a phosphotyrosine-binding domain (PTB)-containing protein interaction motif that also mediates internalization from the cell surface. A similar motif in another BACE1 substrate, APP, controls access of APP to endosomally-localized BACE1. Also similar to APP, the Sez6 intracellular domain is released from the membrane by γ-secretase (Pigoni et al., 2016) through “regulated intramembrane proteolysis”.

All three of the Sez6 family members were initially identified as candidate substrates for BACE1 in neurons using the proteomic SPECS technique (Kuhn et al., 2012). The recent demonstration that Sez6 and Sez6L shedding is essentially abolished by BACE inhibitors as well as in BACE1 knockout and BACE1/2 double knockout mice, validates these proteins as bona fide BACE1 substrates in the brain (Pigoni et al., 2016).

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