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Significance γ-Secretase is a conserved and ubiquitous intramembrane-cleaving protease (I-CLiP). Its normal function is required for proper notch signaling, and its processing of amyloid precursor protein is implicated in Alzheimer’s disease. Although γ-secretase has over 90 reported substrates, little is known about the mechanism by which γ-secretase recruits its substrates while at the same time distinguishing substrate from nonsubstrate within the protein-crowded environment of cellular membranes. In contrast to previous studies, our data demonstrate that substrate transmembrane domain drives its interaction with γ-secretase. We find that the γ-secretase component nicastrin acts to sterically block substrates with large ectodomains from interacting with γ-secretase, providing the mechanism by which γ-secretase selectively recruits ectodomain-shed substrates while also preventing cleavage of nonsubstrates.

Nicastrin functions to sterically hinder γ-secretase–substrate interactions driven by substrate transmembrane domain