The adaptor protein PICK1 targets the sorting receptor SorLA
Lars Binkle1, Marcel Klein1, Uwe Borgmeyer1
1Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany.
Molecular Brain
|February 20, 2022
Summary
SorLA, a receptor linked to Alzheimer's disease, interacts with the cytosolic adaptor protein PICK1. This interaction, mediated by SorLA's C-terminus, influences its intracellular sorting in neurons.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- SorLA is a Vps10p-domain receptor involved in neuronal endosomal sorting and linked to Alzheimer's disease (AD).
- SorLA interacts with various ligands, including amyloid precursor protein and amyloid-beta, and its intracellular trafficking is regulated by cytosolic adaptors.
- SorLA and Sortilin, another Vps10p-D receptor, share some adaptors and ligands but localize to different endosomal compartments, suggesting distinct targeting mechanisms.
Purpose of the Study:
- To investigate the interaction between SorLA and cytosolic adaptors PSD95 and PICK1.
- To determine the specific binding domains and cellular localization of the SorLA-PICK1 interaction.
- To elucidate the role of PICK1 in regulating SorLA's intracellular itinerary and neuronal sorting.
Main Methods:
- Mammalian-two-hybrid assays to detect protein-protein interactions.
- Pull-down experiments to confirm binding between SorLA and PICK1.
- Cellular recruitment and co-localization studies in primary neurons using mutational analysis.
Main Results:
- SorLA specifically interacts with PICK1, but not PSD95.
- The C-terminal PDZ-binding motif VIA of SorLA mediates the interaction with PICK1.
- SorLA and PICK1 co-localize at vesicular structures within primary neurons, indicating a functional relationship.
Conclusions:
- PICK1 is identified as a novel binding partner for SorLA.
- The interaction between SorLA and PICK1 is crucial for regulating SorLA's subcellular localization and endosomal sorting.
- This finding contributes to understanding neuronal endosomal sorting mechanisms and potential therapeutic targets for Alzheimer's disease.
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