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Nicastrin serves as a gatekeeper of the γ-secretase complex. The large ectodomain of nicastrin juts out over the entryway to the active site, sterically preventing access of substrates with ectodomains that are >20 Å long. Conformationally flexible TMD2 of presenilin is believed to be the gate, allowing substrate entry within the membrane. Protein Data Bank entry 5A63.
