9AU7

Human Retriever VPS35L/VPS29/VPS26C complex bound to SNX17 peptide (Composite Map)

Summary for 9AU7

• Entry DOI: 10.2210/pdb9au7/pdb
• EMDB information: 43872
• Descriptor: VPS35 endosomal protein-sorting factor-like, Vacuolar protein sorting-associated protein 29, Vacuolar protein sorting-associated protein 26C, ... (4 entities in total)
• Functional Keywords: retreiver, ccc, endosomal recycling, sorting nexin, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 167840.21

Authors

Chen, B.,Chen, Z.,Han, Y.,Boesch, D.J.,Juneja, P.,Burstein, E.,Fung, H.Y.J. (deposition date: 2024-02-28, release date: 2024-10-30, Last modification date: 2024-12-11)

Primary citation

Singla, A.,Boesch, D.J.,Fung, H.Y.J.,Ngoka, C.,Enriquez, A.S.,Song, R.,Kramer, D.A.,Han, Y.,Banarer, E.,Lemoff, A.,Juneja, P.,Billadeau, D.D.,Bai, X.,Chen, Z.,Turer, E.E.,Burstein, E.,Chen, B.
Structural basis for Retriever-SNX17 assembly and endosomal sorting.
Nat Commun, 15:10193-10193, 2024

PubMed Abstract: 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.

PubMed: 39587083
DOI: 10.1038/s41467-024-54583-6

Experimental method

ELECTRON MICROSCOPY (3.4 Å)