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VARP binds SNX27 to promote endosomal supercomplex formation on membranes
Mintu Chandra1,2, Amy K Kendall1,2, Marijn G J Ford3
1Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
Science Advances
|February 12, 2025
Summary
This study reveals how sorting nexin (SNX) and Retromer coat proteins assemble on endosomes. The protein VARP is crucial for orchestrating this assembly, ensuring proper cargo sorting from endosomes.
Area of Science:
- Cell Biology
- Molecular Biology
- Biophysics
Background:
- Endosomes act as central sorting stations for cellular proteins.
- The assembly mechanisms of metazoan sorting nexin (SNX)/Retromer complexes on endosomal membranes are not fully understood.
Purpose of the Study:
- To elucidate the assembly mechanisms of SNX/Retromer complexes in metazoans.
- To identify the role of VARP in regulating endosomal coat assembly and cargo sorting.
Main Methods:
- Biochemical and biophysical approaches were used.
- AlphaFold modeling identified novel protein interactions.
- Biochemical reconstitution systems with purified proteins were employed.
Main Results:
- A direct interaction between SNX27 and VARP was discovered.
- Specific combinations of Retromer, SNX27, and ESCPE-1 (SNX2/SNX6) were shown to remodel membranes.
- VARP was found to be essential for the in vitro reconstitution of an endosomal "supercomplex".
Conclusions:
- VARP plays a key regulatory role in metazoan endosomal coat assembly.
- This regulation by VARP is critical for efficient cargo sorting out of endosomes.
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