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Intramembraneproteases typically cleave multiple substrates withintheir transmembrane domains （TMDs）. Because substrate TMDs lack aconsensus sequence around their scissile sites, it remains unclearhow the enzyme discriminates substrates from nonsubstrates at thelevel of their TMDs. Here, we compare the previously well investigatedTMDs of γ-secretase substrates C99 and Notch1 in terms of helixflexibility. Our results reveal that the low-stability site neigboringa functionally relevant diglycine hinge of C99 has an equivalent inthe Notch1 TMD. This suggests that the tetra-alanine motif of Notch1also functions as a hinge which may facilitate its cleavage.
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