posted on 2006-02-28, 00:00authored byOlav M. Andersen, Vanessa Schmidt, Robert Spoelgen, Jørgen Gliemann, Joachim Behlke, Denise Galatis, William J. McKinstry, Michael W. Parker, Colin L. Masters, Bradley T. Hyman, Roberto Cappai, Thomas E. Willnow
SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of
the amyloid precursor protein (APP) in neurons. SorLA/LR11-mediated binding results in sequestration
of APP in the Golgi and in protection from processing into the amyloid-β peptide (Aβ), the principal
component of senile plaques in Alzheimer's disease (AD). To gain insight into the molecular mechanisms
governing sorLA and APP interaction, we have dissected the respective protein interacting domains. Using
a fluorescence resonance energy transfer (FRET) based assay of protein proximity, we identified binding
sites in the extracellular regions of both proteins. Fine mapping by surface plasmon resonance analysis
and analytical ultracentrifugation of recombinant APP and sorLA fragments further narrowed down the
binding domains to the cluster of complement-type repeats in sorLA that forms a 1:1 stoichiometric complex
with the carbohydrate-linked domain of APP. These data shed new light on the molecular determinants
of neuronal APP trafficking and processing and on possible targets for intervention with senile plaque
formation in patients with AD.