Molecular Dissection of the Interaction between Amyloid Precursor Protein and Its Neuronal Trafficking Receptor SorLA/LR11
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.
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SORLA binds and sequesters APP in intracellular compartments to reduce Aβ production.
“Another AD risk factor sortilin-related receptor containing LDLR A repeats (SORLA) can bind and sequester APP in intracellular compartments to reduce Aβ production [44].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [44]
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- Authors
- Andersen, O. M., Schmidt, V., Spoelgen, R., Gliemann, J., Behlke, J., Galatis, D., McKinstry, W. J., Parker, M. W., Masters, C. L., Hyman, B. T., Cappai, R., & Willnow, T. E.
- Affiliations
- Mental Health Research Institute (AU)
- Corresponding author
- Andersen, Olav M.
- ORCID
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-02-01
- Volume
- 45
- Issue
- 8
- Pages
- 2618-2628
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W1970082506
- Cited by
- 178
- References
- 18
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 19 · 2019: 7 · 2018: 1 · 2017: 9 · 2016: 12 · 2015: 9 · 2014: 5 · 2013: 5 · 2012: 20
- FWCI
- 8.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amyloid precursor protein, SorLA, LR11, protein-protein interaction, binding domain, amyloid-beta, Alzheimer's disease, amyloid plaques, neuronal trafficking, APP processing
- MeSH terms
- Brain, Cells, Cultured, Humans, Models, Biological, Neurons, Protein Binding, Receptors, LDL, Time Factors, Transfection, Amyloid beta-Protein Precursor, Protein Structure, Tertiary, Microscopy, Confocal, Surface Plasmon Resonance, Protein Transport, LDL-Receptor Related Proteins, Membrane Transport Proteins
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