Table 3.

Typical features of the majority of PS/γ-secretase substrate proteins

1. Type-I transmembrane proteins*

2. Undergo ectodomain shedding by α- and/or β-secretase-like activity prior to PS/γ-secretase-mediated cleavage

3. PS/γ-secretase-mediated RIP at or near the border of transmembrane and cytoplasmic domains

4. PS/γ-secretase cleavage releases substrate ICD from the membrane, some ICDs localize in the nucleus

5. Lack of functional PS/γ-secretase prevents ICD generation and accumulation of substrate CTFs

6. Many ICDs are labile and degraded by the proteasome

^*Exceptions are the glutamate receptor subunit 3 (polytopic membrane protein) and glucosaminyltransferase GnT-V (type-II transmembrane protein).

Abbreviations: ICD, intracellular domain; CTF, C-terminal fragment; RIP, regulated intramembrane proteolysis.