Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing.
Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP.
Yu
G
G
Centre for Research in Neurodegenerative Diseases, Toronto Western Hospital, and Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
Nishimura
M
M
Arawaka
S
S
Levitan
D
D
Zhang
L
L
Tandon
A
A
Song
Y Q
YQ
Rogaeva
E
E
Chen
F
F
Kawarai
T
T
Supala
A
A
Levesque
L
L
Yu
H
H
Yang
D S
DS
Holmes
E
E
Milman
P
P
Liang
Y
Y
Zhang
D M
DM
Xu
D H
DH
Sato
C
C
Rogaev
E
E
Smith
M
M
Janus
C
C
Zhang
Y
Y
Aebersold
R
R
Farrer
L S
LS
Sorbi
S
S
Bruni
A
A
Fraser
P
P
St George-Hyslop
P
P
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; C060620:Glp-1 protein, C elegans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human