Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila.
The transmembrane glycoprotein Nicastrin was identified in a complex with the multipass membrane protein Presenilin. Presenilin mediates transmembrane cleavage of single-pass transmembrane proteins with short extracellular domains, including the ligand-activated form of the receptor Notch and beta-amyloid precursor protein (beta-APP). Transmembrane cleavage of Notch is essential for signal transduction, and transmembrane cleavage of beta-APP generates pathogenic amyloid peptides implicated in Alzheimer's disease. Here, we investigate the requirement for Nicastrin in Presenilin-mediated transmembrane cleavage. We show that, in Drosophila, loss of Nicastrin activity blocks the accumulation of Presenilin associated with the apical plasma membrane, abolishes Presenilin-dependent cleavage of the transmembrane domains of Notch and beta-APP, and abrogates Notch signal transduction.
Chung
H M
HM
Department of Genetics and Development, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Struhl
G
G
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D053764:Presenilin-1; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D053764:Presenilin-1; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases