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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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.[1]


  1. Synergistic effects of Munc18a and X11 proteins on amyloid precursor protein metabolism. Ho, C.S., Marinescu, V., Steinhilb, M.L., Gaut, J.R., Turner, R.S., Stuenkel, E.L. J. Biol. Chem. (2002) [Pubmed]
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