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J. Biol. Chem., Vol. 277, Issue 30, 27021-27028, July 26, 2002
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From the Departments of X11 proteins have been shown to modulate
metabolism of the amyloid precursor protein (APP) and to reduce the
secretion of
Synergistic Effects of Munc18a and X11 Proteins on Amyloid
Precursor Protein Metabolism*
,,
, and**
Physiology and
¶ Neurology, § Institute of Gerontology and Department
of Biological Chemistry, University of Michigan Medical Center, Ann
Arbor, Michigan 48109 and the Veterans Affairs Medical
Center, Geriatric Research, Education, and Clinical Center,
Ann Arbor, Michigan 48105
-amyloid peptides (A) that are associated with
Alzheimer's disease. Whereas X11
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
X11, Munc18a potentiated the retention of APP and suppression of
A secretion by X11. As a result, the constitutive release of
A40 was nearly abolished. Experiments using N terminus deletion
mutants of X11/ and the MID-deficient X11
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
-secretase activity, whereas it also intensified the reduction in
A40 secretion by X11. These data indicate that Munc18a in concert
with X11 acts to suppress -secretase processing. We conclude that
Munc18a acts through direct and indirect interactions with X11 proteins
and powerfully regulates APP metabolism and A secretion.
*
This work was supported by National Institutes of Health
Grants NS36227 (to E. L. S.) and NS11103 (to C. S. H.) from the NINDS, a pilot grant from the Michigan Alzheimer's
Disease Research Center (to E. L. S.), and National
Institutes of Health Grant P50 AG08671 (to R. S. T.) from the
NIA.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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