Structural basis for Retriever-SNX17 assembly and endosomal sorting
During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens.
Authors
- Baoyu Chen (ORCID: https://orcid.org/0000-0002-6366-159X)
- Xiao‐chen Bai (ORCID: https://orcid.org/0000-0002-4234-5686)
- Puneet Juneja (ORCID: https://orcid.org/0000-0002-8934-4509)
- Ran Song (ORCID: https://orcid.org/0000-0002-1564-527X)
- Andrew S. Lemoff (ORCID: https://orcid.org/0000-0002-4943-0170)
- Ezra Burstein (ORCID: https://orcid.org/0000-0003-4341-6367)
- Daniel A. Kramer (ORCID: https://orcid.org/0000-0002-7159-9562)
- Emre E. Turer (ORCID: https://orcid.org/0000-0001-8782-3648)
- Yan Han (ORCID: https://orcid.org/0000-0002-1207-7756)
- Ho Yee Joyce Fung (ORCID: https://orcid.org/0000-0002-0502-1957)
- Daniel D. Billadeau (ORCID: https://orcid.org/0000-0002-2296-9547)
- Daniel J. Boesch (ORCID: https://orcid.org/0009-0003-1656-9453)
- Chigozie Ngoka
- Avery S. Enriquez
- Zhe Chen (ORCID: https://orcid.org/0000-0002-1668-4051)
- Amika Singla (ORCID: https://orcid.org/0000-0002-9454-9111)
- Esther Banarer
Institutions
- Mayo Clinic (US)
- Iowa State University (US)
- Southwestern Medical Center (US)
- Thermo Fisher Scientific (United States) (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s41467-024-54583-6
- Citations
- 15
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 3.51
Funders
- National Science Foundation
- U.S. Department of Energy
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- Yale University
- Oregon Health and Science University
- University of Texas Southwestern Medical Center
- Iowa State University
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- Biological and Environmental Research