Nicastrin functions as a gamma-secretase-substrate receptor.
gamma-secretase catalyzes the intramembrane cleavage of amyloid precursor protein (APP) and Notch after their extracellular domains are shed by site-specific proteolysis. Nicastrin is an essential glycoprotein component of the gamma-secretase complex but has no known function. We now show that the ectodomain of nicastrin binds the new amino terminus that is generated upon proteolysis of the extracellular APP and Notch domains, thereby recruiting the APP and Notch substrates into the gamma-secretase complex. Chemical- or antibody-mediated blocking of the free amino terminus, addition of purified nicastrin ectodomain, or mutations in the ectodomain markedly reduce the binding and cleavage of substrate by gamma-secretase. These results indicate that nicastrin is a receptor for the amino-terminal stubs that are generated by ectodomain shedding of type I transmembrane proteins. Our data are consistent with a model where nicastrin presents these substrates to gamma-secretase and thereby facilitates their cleavage via intramembrane proteolysis.
Shah
Sanjiv
S
Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Lee
Sheu-Fen
SF
Tabuchi
Katsuhiko
K
Hao
Yi-Heng
YH
Yu
Cong
C
LaPlant
Quincey
Q
Ball
Haydn
H
Dann
Charles E
CE
Südhof
Thomas
T
Yu
Gang
G
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology; D010450:Endopeptidases; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051880:Receptors, Notch; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D011994:Recombinant Proteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse