PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling.
Presenilin proteins play critical roles in the proteolytic processing of both Notch and amyloid precursor protein (APP). Presenilin itself undergoes endoproteolytic processing to generate an N-terminal and C-terminal fragment. As demonstrated previously, overexpression of presenilin 1 (PS1) holoprotein does not change the levels of the N-terminal and C-terminal fragments (NTF and CTF). When we coexpress the PS1 NTF and CTF, marked increases in the cellular levels of these fragments are seen. By coexpressing the PS1 NTF and CTF, we demonstrate conclusively that a noncovalent complex of the NTF and CTF is the active species of presenilin. However, although the PS1 NTF/CTF complex is necessary for gamma-secretase activity, it is not sufficient. Independent overexpression of the PS1 NTF and CTF was also used to show that the Asp-257 and Asp-385 mutations in PS1 decrease Abeta production by a direct effect on gamma-secretase activity and not by the inhibition of PS1 endoproteolysis.
Levitan
D
D
Schering-Plough Research Institute, Department of Central Nervous System/Cardiovascular, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. diane.levitan@sp
Lee
J
J
Song
L
L
Manning
R
R
Wong
G
G
Parker
E
E
Zhang
L
L
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism; D015870:Gene Expression; D015801:Helminth Proteins / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D010446:Peptide Fragments; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*; D018411:Spodoptera / Q000166:cytology
D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D051880:Receptors, Notch; C095907:SEL-12 protein, C elegans; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human