title: Synergistic effects of Munc18a and X11 proteins on amyloid precursor protein metabolism.
abstract: 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.
authors.affiliation: Department of Physiology, Institute of Gerontology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Chi S
authors.initials: CS
authors.lastname: Ho
authors.forename: Vlad
authors.initials: V
authors.lastname: Marinescu
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Steinhilb
authors.forename: James R
authors.initials: JR
authors.lastname: Gaut
authors.forename: R Scott
authors.initials: RS
authors.lastname: Turner
authors.forename: Edward L
authors.initials: EL
authors.lastname: Stuenkel
mesh_terms: 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
chemical_list: 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