Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.
gamma-Secretase catalyzes the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. This unusual protease has eluded identification, though evidence suggests that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. The formation of presenilin heterodimers from the holoprotein is tightly gated by unknown limiting cellular factors. Here we show that Aph-1 and Pen-2, two recently identified membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Coexpression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity. These findings suggest that the four membrane proteins comprise the limiting components of gamma-secretase and coassemble to form the active enzyme in mammalian cells.
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
W Taylor
WT
Kimberly
Matthew J
MJ
LaVoie
Beth L
BL
Ostaszewski
Wenjuan
W
Ye
Michael S
MS
Wolfe
Dennis J
DJ
Selkoe
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D006224:Cricetinae; D003412:Cricetulus; D010450:Endopeptidases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*
C405066:APH-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases