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The Journal of Neuroscience, November 1, 2001, 21(21):8354-8361
Demonstration by Fluorescence Resonance Energy Transfer of
Two Sites of Interaction between the Low-Density Lipoprotein
Receptor-Related Protein and the Amyloid Precursor Protein: Role
of the Intracellular Adapter Protein Fe65
Ayae
Kinoshita1,
Christa M.
Whelan1,
Carolyn
J.
Smith1,
Irena
Mikhailenko2,
G. William
Rebeck1,
Dudley K.
Strickland2, and
Bradley T.
Hyman1
1 Alzheimer's Disease Research Unit, Department of
Neurology, Massachusetts General Hospital, Charlestown, Massachusetts
02129, and 2 Department of Vascular Biology, Holland
Laboratory, American Red Cross, Rockville, Maryland 20855
Amyloid- , the major constituent of senile plaques in
Alzheimer's disease, is derived from the amyloid precursor protein
(APP) by proteolysis. Kunitz protease inhibitor (KPI) containing forms of APP (APP751/770) interact with a multifunctional endocytic receptor,
the low-density lipoprotein receptor-related protein (LRP), which
modulates its proteolytic processing affecting production of
amyloid-. We used fluorescence resonance energy transfer (FRET) using labeled LRP and APP in H4 cell line to examine the subcellular localization and the molecular domains involved in the APP-LRP interaction. KPI-containing forms of APP (APP770) demonstrated FRET
with LRP that was sensitive to the LRP inhibitor receptor-associated protein (RAP), suggesting an interaction between the extracellular domains of APP770 and LRP. APP695 also interacts with LRP to lesser degree (as measured by extracellular domain probes), and this ectodomain interaction is not altered by RAP. By using C-terminally tagged LRP and APP, we demonstrate a second site of interaction between
the C termini of both APP695 and APP770 and the C terminus of LRP, and
that the interactions at these regions are not sensitive to RAP. We
next examined the possibility that the C-termini APP-LRP interaction
was mediated by Fe65, an adaptor protein that interacts with the
cytoplasmic tails of LRP and APP. FRET studies confirmed a close
proximity between the amino Fe65 phosphotyrosine binding (PTB)
domain and LRP cytoplasmic domain and between the carboxyl Fe65 PTB
domain and the APP cytoplasmic domain. These findings demonstrate that
LRP interaction with APP occurs via both extracellular and
intracellular protein interaction domains.
Key words:
amyloid precursor protein; APP; low-density lipoprotein
receptor-related protein; LRP; adaptor protein Fe65; fluorescent
resonance energy transfer; FRET; protein-protein interaction; secretory pathway; immunocytochemistry; confocal microscopy
Copyright © 2001 Society for Neuroscience 0270-6474/01/21218354-08$05.00/0
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