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Nicastrin functions as a gamma-secretase-substrate receptor
Sanjiv Shah1, Sheu-Fen Lee, Katsuhiko Tabuchi
1Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cell
|August 13, 2005
Summary
Nicastrin acts as a receptor for amyloid precursor protein (APP) and Notch substrates. Its ectodomain binds cleaved substrates, recruiting them to the gamma-secretase complex for intramembrane proteolysis.
Area of Science:
- Molecular and Cellular Biology
- Neuroscience
Background:
- Gamma-secretase performs intramembrane cleavage of amyloid precursor protein (APP) and Notch.
- Nicastrin is a known component of the gamma-secretase complex with an undefined role.
Purpose of the Study:
- To elucidate the function of nicastrin within the gamma-secretase complex.
- To investigate how substrates are recruited for gamma-secretase-mediated cleavage.
Main Methods:
- Investigated the interaction between nicastrin ectodomain and substrate amino termini.
- Utilized chemical and antibody blocking strategies.
- Performed mutational analysis of the nicastrin ectodomain.
Main Results:
- Nicastrin's ectodomain binds the newly generated amino terminus of cleaved APP and Notch substrates.
- This binding facilitates the recruitment of substrates into the gamma-secretase complex.
- Blocking this interaction or mutating nicastrin ectodomain reduces substrate binding and cleavage.
Conclusions:
- Nicastrin functions as a receptor for amino-terminal stubs of type I transmembrane proteins after ectodomain shedding.
- Nicastrin presents these substrates to gamma-secretase, promoting their intramembrane proteolysis.
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