PT  - JOURNAL ARTICLE
AU  - Minsuk Kwak
AU  - Kaden M. Southard
AU  - Nam Hyeong Kim
AU  - Ramu Gopalappa
AU  - Woon Ryoung Kim
AU  - Minji An
AU  - Hyun Jung Lee
AU  - Justin Farlow
AU  - Anastasios Georgakopoulos
AU  - Nikolaos K. Robakis
AU  - Daeha Seo
AU  - Hyeong Bum Kim
AU  - Yong Ho Kim
AU  - Jinwoo Cheon
AU  - Zev J. Gartner
AU  - Young-wook Jun
TI  - Size-dependent protein segregation creates a spatial switch for Notch and APP signaling
AID  - 10.1101/2020.06.28.176560
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.28.176560
4099  - http://biorxiv.org/content/early/2020/07/02/2020.06.28.176560.short
4100  - http://biorxiv.org/content/early/2020/07/02/2020.06.28.176560.full
AB  - Aberrant cleavage of Notch and amyloid precursor proteins (APPs) by γ-secretase is implicated in numerous diseases, but how cleavage is regulated in space and time is unclear. Here, we report that cadherin-based adherens junctions (cadAJs) are sites of high cell-surface γ-secretase activity, while simultaneously excluding these γ-secretase substrates by a size-dependent mechanism, prohibiting enzyme-substrate interactions. Upon activation, Notch and APP undergo drastic spatial rearrangements to cadAJs, concentrating them with γ-secretase, wherein they are further processed for downstream signaling. Spatial mutation by decreasing (or increasing) the size of Notch extracellular domain promotes (or inhibits) signaling, respectively. Dysregulation of this spatial switch also promotes formation of more amyloidogenic Aβ. Therefore, cadAJs creates distinct biochemical compartments regulating signaling events involving γ-secretase and prevent pathogenic activation of its substrates.Competing Interest StatementThe authors have declared no competing interest.