Synergistic effects of Munc18a and X11 proteins on amyloid precursor protein metabolism.
X11 proteins have been shown to modulate metabolism of the amyloid precursor protein (APP) and to reduce the secretion of beta-amyloid peptides (Abeta) that are associated with Alzheimer's disease. Whereas X11alpha interacts with APP via its phosphotyrosine-binding domain, recent reports indicate that additional regulatory interactions involve the N terminus of X11. Here we report that the syntaxin-1a-binding protein Munc18a, which interacts with the Munc18a-interacting domain (MID) at the N terminus of X11, strongly regulates the actions of X11 on APP metabolism. When co-expressed with X11alpha, Munc18a potentiated the retention of APP and suppression of Abeta secretion by X11alpha. As a result, the constitutive release of Abeta40 was nearly abolished. Experiments using N terminus deletion mutants of X11alpha/beta and the MID-deficient X11gamma revealed that the majority of the regulatory effect by Munc18a occurred independent of a direct interaction of Munc18a with X11, although the presence of X11 was required. Munc18a expression induced a small increase in beta-secretase activity, whereas it also intensified the reduction in Abeta40 secretion by X11alpha. These data indicate that Munc18a in concert with X11 acts to suppress gamma-secretase processing. We conclude that Munc18a acts through direct and indirect interactions with X11 proteins and powerfully regulates APP metabolism and Abeta secretion.
Ho
Chi S
CS
Department of Physiology, Institute of Gerontology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Marinescu
Vlad
V
Steinhilb
Michelle L
ML
Gaut
James R
JR
Turner
R Scott
RS
Stuenkel
Edward L
EL
D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D005089:Exocytosis; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D008954:Models, Biological; D051938:Munc18 Proteins; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D033921:Vesicular Transport Proteins
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C513071:Apba1 protein, rat; D008565:Membrane Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D033921:Vesicular Transport Proteins; D005982:Glutathione Transferase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D002118:Calcium