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Fig. 2. Type I membrane proteins as substrates for PS-mediated {gamma}-secretase cleavage. APP, Notch, ErbB-4, E-cadherin, CD44, LRP and nectin1{alpha} are type I membrane proteins. APP, Notch and CD44 can be cleaved at the middle of TM domains and at a residue close to the interface of membrane and cytoplasm (red arrows). Cleavage of ErbB-4 occurs at several residues from the membrane-cytoplasm boundary, and cleavage of E-cadherin occurs right at the interface. LRP and nectin 1{alpha} undergo proteolysis in the TM domain to release the intracellular domain. Ectodomain shedding of FL membrane proteins (blue arrow) is required for subsequent intramembrane proteolysis mediated by PS.