Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma - Evidence for distinct mechanisms involved in gamma-secretase processing or the APP and Notch1 transmembrane domains
Cj. Yu et al., Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma - Evidence for distinct mechanisms involved in gamma-secretase processing or the APP and Notch1 transmembrane domains, J BIOL CHEM, 276(47), 2001, pp. 43756-43760
A variety of investigations have led to the conclusion that presenilins (PS
) play a critical role in intramembranous, gamma -secretase proteolysis of
selected type I membrane proteins, including Notch1 and amyloid precursor p
rotein (APP). We now show that the generation of the S3/Notch intracellular
domain and APP-carboxyl-terminal fragment gamma (CTF gamma) derivatives ar
e dependent on PS expression and inhibited by a highly selective and potent
gamma -secretase inhibitor. Unexpectedly, the APP-CTF-gamma derivative is
generated by processing between Leu-645 and Val-646 (of APP(695)), several
amino acids carboxyl-terminal to the scissile bonds for production of amylo
id beta protein peptides. Although the relationship of APP-CTF gamma to the
production of amyloid beta protein peptides is not known, we conclude that
in contrast to the highly selective PS-dependent processing of Notch, the
PS-dependent gamma -secretase processing of APP is largely nonselective and
occurs at multiple sites within the APP transmembrane domain.