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Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11

Item Type:Article
Title:Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11
Creators Name:Andersen, O.M. and Schmidt, V. and Spoelgen, R. and Gliemann, J. and Behlke, J. and Galatis, D. and McKinstry, W.J. and Parker, M.W. and Masters, C.L. and Hyman, B.T. and Cappai, R. and Willnow, T.E.
Abstract: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-beta peptide (Abeta), 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.
Keywords:Amyloid beta-Protein Precursor, Brain, Cultured Cells, LDL-Receptor Related Proteins, Membrane Transport Proteins, Confocal Microscopy, Biological Models, Neurons, Protein Binding, Tertiary Protein Structure, Protein Transport, LDL Receptors, Surface Plasmon Resonance, Time Factors, Transfection
Source:Biochemistry
ISSN:0006-2960
Publisher:American Chemical Society (U.S.A.)
Volume:45
Number:8
Page Range:2618-2628
Date:28 February 2006
Official Publication:https://doi.org/10.1021/bi052120v
PubMed:View item in PubMed

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