Selective cargo and membrane recognition by SNX17 regulates its interaction with Retriever

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Trafficking

Background:

• The Retriever complex facilitates transmembrane protein recycling from endosomes to the plasma membrane.
• The cargo adapter protein SNX17 is known to recruit Retriever to endosomal membranes, but the interaction mechanism is unclear.

Purpose of the Study:

• To elucidate the molecular details of the interaction between SNX17 and the Retriever complex.
• To understand how SNX17 binding to cargo and membranes regulates Retriever recruitment.

Main Methods:

• Biophysical studies using recombinant proteins and liposomes.
• Structural model-guided mutagenesis.
• Analysis of SNX17-Retriever interactions in solution and on membranes.

Main Results:

• Demonstrated a direct interaction between SNX17's C-terminal region and the VPS35L/VPS26C interface of Retriever.
• Showed that cargo binding to SNX17 enhances this interaction by disrupting autoinhibition.
• Identified cargo-independent Retriever recruitment mediated by SNX17 binding to phosphatidylinositol-3-phosphate on membranes.

Conclusions:

• SNX17 utilizes dual activation mechanisms to modulate Retriever recruitment.
• Cargo and membrane binding activate SNX17, promoting efficient protein recycling at endosomes.